Compounds and methods of use thereof

ABSTRACT

Indole compounds are disclosed. Also disclosed are methods for using the compounds to treat human and animal disease, pharmaceutical compositions of the compounds, and kits including the compounds.

RELATED APPLICATIONS

This application is a Continuation of Ser. No. 12/853,782, filed on Aug.10, 2010, which claims priority to U.S. Provisional Application Ser. No.61/232,772, filed on Aug. 10, 2009, each of which is incorporated byreference herein in its entirety.

BACKGROUND OF THE INVENTION

Serotonin (5-hydroxytryptamine, 5-HT) plays a significant role ininfluencing a large number of central and peripheral processes.5-HT-selective pharmacotherapies have been developed to treat a widevariety of medical problems including depression, anxiety,schizophrenia, migraine, emesis, and appetite control (Annual Reports inMedicinal Chemistry, Volume 32, 2002, Academic Press, Fitzgerald, L.,Ennis, M. “5-HT_(2C) Receptor Modulators: Progress in Development of NewCNS Medicines” pp 21-30). 5-HT exerts its influence through activationof fourteen distinct receptor subtypes in seven separate families(5-HT₁, 5-HT₂, 5-HT₃, 5-HT₄, 5-HT₅, 5-HT₆, 5-HT₇).

Each of the seven families may also encompass various subtypes. Forexample, the 5-HT₁ family includes subtypes 5-HT_(IA), 5-HT_(IB),5-HT_(ID), 5-HT_(IE) and 5-HT_(1F). The 5-HT₂ family includes 5-HT_(2A),5-HT_(2B) and 5-HT_(2C). Lastly, the 5-HT₃ family includes 5-HT_(3A) and5-HT_(3B) while the 5-HT₅ family includes 5-HT_(5A). While the 5-HT₁,5-HT2 and 5-HT3 families have been studied most extensively, each familyhas been linked to various disease indications as discussed below.

Modulation of the 5-HT family of receptors has been shown to play a rolein numerous human diseases including obesity, obsessive-compulsivedisorder (OCD), sexual dysfunction, epilepsy, schizophrenia, and anxietydisorders (Roth, B., Shapiro, D. “Insights into the Structure andFunction of 5-HT2 Family Serotonin Receptors Reveal Novel Strategies forTherapeutic Target Development” Expert Opin. Ther. Targets 2001, 5, 685;Martin, J., Bos, M., Jenck, F., Moreau, J-1., Mutel, V., Sleight, A.,Wichmann, J., Andrews, J., Berendsen, H., Broekkamp, C., Ruight, G.,Kohler, C., van Delft, A. “5-HT_(2C) Receptor Agonists: PharmacologicalCharacteristics and Therapeutic Potential” J. Pharm. Experimental Ther.1998, 286, 913; Tecott, L., Sun, L., Akana, S., Strack, A., Lowenstein,D., Dallman, M., Julius, D. “Eating Disorder and Epilepsy in MiceLacking 5-HT_(2C) Serotonin Receptors” Nature 1995, 374, 542). Aclinical study in 1997 (Sargent, P., Sharpley, A., Williams, C., Cowen,P. “5-HT_(2C)-Receptor Activation Decreases Appetite and Body Weight inObese Subjects” Psychopharmacology 1997, 133, 309; Barnes, Nicholas M.,Sharp, Trevor “A Review of Central 5-HT Receptors and Their Function”Neuropharmacology 1999, 38, 1038). However, a need for potent andselective 5-HT modulators (specifically those associated with 5-HT_(2A),5-HT_(2C) and 5-HT₆) still exists

SUMMARY

Described herein are compounds, pharmaceutical compositions containingthe compounds and method of using the compounds to treat a disorder,e.g., a 5-HT related disorder, in a subject. For example a disorderassociated with regulation of or expression of 5-HT_(2A), 5-HT_(2C) and5-HT₆.

In one aspect, the invention is directed to a compound selected from thefollowing formula:

wherein

R^(1a) and R^(2a) are each independently selected from H, optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted arylalkyl, optionallysubstituted heteroaralalkyl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocycloalkyl;

R³ is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, halogen, or—C(O)NR^(d)R^(d′);

W is

optionally substituted aryl, optionally substituted heteroaryl,optionally substituted arylC₂-C₆alkyl, optionally substitutedheterocyclyl, optionally substituted cycloalkyl; optionally substitutedheteroarylalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocycloalkyl, optionally substituted arylheteroalkyl,optionally substituted heteroarylheteroalkyl, optionally substitutedheterocyclylheteroalkyl, optionally substituted cycloalkylheteroalkyl,-alkyl-O—C₀₋₂alkyl-aryl, -alkyl-O—C₀₋₂alkyl-heteroaryl,—C(O)NR^(d)R^(d′), C₁ alkyl substituted with —C(O)NR^(d)R^(d′), or C₂₋₈alkyl substituted with —NR^(d)R^(d′), —C(O)NR^(d)R^(d′) or —OR^(d);

A is optionally substituted C₁₋₄ alkylene, optionally substitutedcycloalkylene, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted arylene, optionally substitutedheteroarylene, or optionally substituted heterocycloalkylene, whereinarylene or heteroarylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, C₃₋₈ cycloalkyl, —OR^(d), C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂arylalkyl, —S(O)₀₋₂ heteroarylalkyl), —S(O)₀₋₂ cycloalkyl, —S(O)₀₋₂heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″)—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d), whereinalkylene and cycloalkylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, oxo, optionally substituted C₁₋₆ alkyl,—S(O)₀₋₂alkyl, —OR^(d) and —NR^(d)R^(d′), aryl, heteroaryl, and C₃-C₈cycloalkyl or 4-8 membered heterocyclyl (e.g., wherein two substituents,together with the carbon to which they are attached, form a ring);

R⁴ is selected from optionally substituted C₁₋₈ alkyl, optionallysubstituted C₁₋₈ heteroalkyl, optionally substituted C₂₋₈ alkenyl, C₂₋₈alkynyl, —S(O)₂ alkyl, —S(O)₂ heteroalkyl, —S(O)₂ aryl, —S(O)₂heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂ heterocyclyl, —S(O)₂heterocycloalkyl, —S(O)₂ arylalkyl, —S(O)₂ heteroarylalkyl, —S(O)₂cycloalkyalkyl, formyl, —OR^(d), —NR^(d)R^(d′), —C(O)OR^(a),—C(O)NR^(d)R^(d′), —S(O)₂NR^(d)R^(d′), amine-substituted C₂₋₆ alkyl,NR^(d′)R^(d″)-substituted C₂₋₆ alkyl, C₃₋₈ cycloalkyl, heterocyclyl,cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl, arylalkyl, andheteroarylalkyl, wherein the alkyl, cycloalkyl and heterocyclyl areoptionally substituted with 1-3 substituents, halo, alkyl, haloalkyl,heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryl and heteroaryl areoptionally substituted with 1-3 substituents, each of which isindependently selected from the group consisting of halogen, alkyl,heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂-arylalkyl, —S(O)₀₋₂-heteroarylalkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —OR^(d), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), optionally substituted—C₁alkyl-C(O)NR^(e)R^(f), —C₂alkyl-O-aryl, —C₂alkyl-O-heteroaryl,—C₁alkyl-heterocyclyl, —C₁alkyl-cycloalkyl, cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl-NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d);

R⁵ is selected from H, halo, and R⁶;

each R⁶ is independently selected from halo, C₁₋₈ alkyl, aryl,heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ arylalkyl, —S(O)₀₋₂ heteroarylalkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂—C₁₋₄alkyl-aryl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′) cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

each of R⁷ and R⁸ is independently H, optionally substituted C₁₋₈ alkylor fluoro; or R⁷ and R⁸ can, together with the carbon to which they areattached, form a ring;

R^(a), and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted cycloalkylalkyl and optionallysubstituted heterocycloalkyl;

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety;

g is 1, 2 or 3;

m is 0, 1, 2, 3, 4 or 5; and

wherein when m is 0, at least one of R⁷ or R⁸ is not H.

In some embodiments, R^(1a) and R^(2a) are each independently selectedfrom H, C₁₋₈ alkyl, or optionally substituted aryl.

In some embodiments, A is selected from optionally substituted C₁₋₄alkylene, wherein the C₁₋₄ alkylene is optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, hydroxyl, optionally substituted C₁₋₆ alkyl, C₁₋₈alkoxy, —SO₂ alkyl, and —NR^(d)R^(d″).

In some embodiments, A is optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted aryl. The compoundmay be optionally substituted heteroaryl, the optionally substitutedheteroarylalkyl, or the optionally substituted aryl is substituted with1-3 substituents, each of which is independently selected from the groupconsisting of halogen, C₃₋₈ cycloalkyl, —OR^(d), C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂arylalkyl, —S(O)₀₋₂ heteroarylalkyl), —S(O)₀₋₂ cycloalkyl, —S(O)₀₋₂heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′) optionally substituted —C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O).

In some embodiments, R³ is selected from H, and optionally substitutedC₁₋₈ alkyl.

In some embodiments, R⁴ is selected from optionally substituted C₁₋₈alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amine-substitutedC₂₋₆ alkyl, NR^(d′)R^(d″)-substituted C₂₋₆ alkyl, —S(O)₂ alkyl, —S(O)₂arylalkyl, —S(O)₂ heteroarylalkyl, —S(O)₂ aryl, —S(O)₂ heteroaryl,—S(O)₂ cycloalkyl, —S(O)₂ heterocycloalkyl, —S(O)₂heterocycloalkylalkyl, —S(O)₂ cycloalkylalkyl, optionally substituted—C₁alkyl-C(O)NR^(e)R^(f), —C₂alkyl-O-aryl, —C₂alkyl-O-heteroaryl,—C₁alkyl-heterocyclyl, and —C₁alkyl-cycloalkyl.

In some embodiments, R⁴ is C₁₋₈ alkyl, cycloalkyl, or heterocyclyloptionally substituted with 1-3 substituents selected from halo, alkyl,haloalkyl, heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryl orherteroaryl are optionally substituted with 1-3 substituents, each ofwhich is independently selected from the group consisting of halogen,alkyl, heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈haloalkoxy, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂-arylalkyl, —S(O)₀₋₂-heteroarylalkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —OR^(d), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′) optionally substituted C₂₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d).

In some embodiments, R⁴ is optionally substituted C₁₋₈ alkyl.

In some embodiments, W is arylC₂₋₈alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′), or —C(O)NR^(d)R^(d′).

In some embodiments, W is

optionally substituted arylC₂-C₆alkyl, or heteroarylalkyl.

In some embodiments, W is optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, or optionally substituted aryl.

In some embodiments, W is optionally substituted heteroarylalkyl.

In some embodiments, W is —(CH₂)₂—O-phenyl.

In some embodiments, W is

In some embodiments, W is

In some embodiments, each R⁵ is selected from C₁₋₈ alkyl, C₁₋₈fluoroalkyl, hydroxyl, C₁₋₈ alkoxy, C₁₋₈ fluoroalkoxy, nitro, halogen,and —NR^(d)R^(d′).

In some embodiments, each R⁵ is halo, C₁₋₈ alkyl or C₁₋₈ haloalkyl.

In some embodiments, each R⁶ is selected from halogen, C₁₋₈ alkyl,hydroxyl, —C₁₋₈ fluoroalkyl, C₁₋₈ haloalkoxy, and —NR^(d)R^(d′).

In some embodiments, each R⁶ is halogen.

In some embodiments, each R⁶ is C₁₋₈ alkyl.

In some embodiments, the compound is:

and optionally m=1, and, optionally, g=1.

In some embodiments, the compound is

wherein X is a halogen, optionally fluorine.

In some embodiments, the compound selected from

wherein X is a halogen, optionally fluorine. Optionally m=1.

In some embodiments, the compound is:

wherein Ar is optionally substituted aryl or optionally substitutedheteroaryl.

In some embodiments, the compound is selected from

wherein Ar is optionally substituted aryl or optionally substitutedheteroaryl.

In some embodiments, W is

wherein m is 1-3, R⁷ and R⁸ are H, and R⁵ is selected from F, Cl, Br,CF₃, methyl, OH, —OCH₃, —OCF₃, and —S(O)₀₋₂R^(a).

In some embodiments, the compound is selected from the group consistingof2-(1-ethyl-6-fluoro-4-(4-fluorobenzyloxy)-1H-indol-3-yl)-N,N-dimethylethanamine,2-(1-ethyl-6-fluoro-4-(4-methoxybenzyloxy)-1H-indol-3-yl)-N,N-dimethylethanamine,2-(4-(4-chlorobenzyloxy)-1-ethyl-6-fluoro-1H-indol-3-yl)-N,N-dimethylethanamine,2-(1-ethyl-6-fluoro-4-(4-(trifluoromethoxy)benzyloxy)-1H-indol-3-yl)-N,N-dimethylethanamine,2-(1-ethyl-6-fluoro-4-(4-(trifluoromethyl)benzyloxy)-1H-indol-3-yl)-N,N-dimethylethanamine,2-(1-ethyl-6-fluoro-4-(2-(trifluoromethyl)benzyloxy)-1H-indol-3-yl)-N,N-dimethylethanamine,2-(1-ethyl-6-fluoro-4-(3-(trifluoromethyl)benzyloxy)-1H-indol-3-yl)-N,N-dimethylethanamine,2-(3-(2-(dimethylamino)ethyl)-1-ethyl-7-fluoro-1H-indol-4-yloxy)aniline,2-(1-ethyl-7-fluoro-4-(2-nitrophenoxy)-1H-indol-3-yl)-N,N-dimethylethanamine,2-(1-ethyl-6-fluoro-4-(5-fluoro-2-methylbenzyloxy)-1H-indol-3-yl)-N,N-dimethylethanamine,2-(1-ethyl-6-fluoro-4-(pyridin-4-ylmethoxy)-1H-indol-3-yl)-N,N-dimethylethanamine,2-(1-ethyl-6-fluoro-4-(thiophen-3-ylmethoxy)-1H-indol-3-yl)-N,N-dimethylethanamine,2-(5-fluoro-1-methyl-4-phenethoxy-1H-indol-3-yl)-N,N-dimethylethanamine,2-(1-ethyl-6-fluoro-4-phenoxy-1H-indol-3-yl)-N,N-dimethylethanamine,2-(4-(2-chlorobenzyloxy)-6-fluoro-1-methyl-1H-indol-3-yl)-N-methylethanamine,2-(4-(4-chlorobenzyloxy)-6-fluoro-1-methyl-1H-indol-3-yl)-N-methylethanamine,2-(4-(3-chlorobenzyloxy)-6-fluoro-1-methyl-1H-indol-3-yl)-N-methylethanamine,2-(4-(3-chlorobenzyloxy)-5-fluoro-1-methyl-1H-indol-3-yl)-N-methylethanamine,2-(4-(4-chlorobenzyloxy)-5-fluoro-1-methyl-1H-indol-3-yl)-N-methylethanamine,2-(5-fluoro-1-methyl-4-(3-(trifluoromethyl)benzyloxy)-1H-indol-3-yl)-N-methylethanamine,2-(5-fluoro-1-methyl-4-(2-methylbenzyloxy)-1H-indol-3-yl)-N-methylethanamine,2-(4-(2-chlorobenzyloxy)-5-fluoro-1-methyl-1H-indol-3-yl)-N-methylethanamine,2-(5-fluoro-4-(2-fluorobenzyloxy)-1-methyl-1H-indol-3-yl)-N-methylethanamine,2-(5-fluoro-4-(4-methoxyphenethoxy)-1-methyl-1H-indol-3-yl)-N-methylethanamine,2-(5-fluoro-1-methyl-4-phenethoxy-1H-indol-3-yl)-N-methylethanamine,2-(5-fluoro-1-methyl-4-(4-methylbenzyloxy)-1H-indol-3-yl)-N-methylethanamine,2-(5-fluoro-4-(4-fluorophenethoxy)-1-methyl-1H-indol-3-yl)-N-methylethanamine,2-(4-(4-chlorophenethoxy)-5-fluoro-1-methyl-1H-indol-3-yl)-N-methylethanamine,2-(4-(biphenyl-2-ylmethoxy)-5-fluoro-1-methyl-1H-indol-3-yl)-N-methylethanamine,2-(5-fluoro-1-methyl-4-(2-(trifluoromethyl)benzyloxy)-1H-indol-3-yl)-N-methylethanamine,2-(5-fluoro-1-methyl-4-(1-phenylethoxy)-1H-indol-3-yl)-N-methylethanamine,2-((3-(2-((2-cyanobenzyl)(methyl)amino)ethyl)-5-fluoro-1-methyl-1H-indol-4-yloxy)methyl)benzonitrile,2-(5-fluoro-4-(5-fluoro-2-methylbenzyloxy)-1-methyl-1H-indol-3-yl)-N-methylethanamine,2-(5-fluoro-1-methyl-4-(2-(trifluoromethoxy)benzyloxy)-1H-indol-3-yl)-N-methylethanamine,2-(5-fluoro-4-(4-fluorobenzyloxy)-1-methyl-1H-indol-3-yl)-N-methylethanamine,2-(5-fluoro-1-methyl-4-(naphthalen-1-ylmethoxy)-1H-indol-3-yl)-N-methylethanamine,1-(2-chlorophenyl)-2-(5-fluoro-1-methyl-3-(2-(methylamino)ethyl)-1H-indol-4-yloxy)ethanol,2-(5-fluoro-1-methyl-4-(4-(methylsulfonyl)benzyloxy)-1H-indol-3-yl)-N-methylethanamine,2-(5-fluoro-4-(naphthalen-1-ylmethoxy)-1-propyl-1H-indol-3-yl)-N-methylethanamine,2-(4-(4-chlorobenzyloxy)-5-fluoro-1-propyl-1H-indol-3-yl)-N-methylethanamine,2-(5-fluoro-1-methyl-4-(quinolin-8-ylmethoxy)-1H-indol-3-yl)-N-methylethanamine,2-(5-fluoro-1-methyl-4-(2-phenoxyethoxy)-1H-indol-3-yl)-N-methylethanamine,2-(5-fluoro-4-(4-fluorobenzyloxy)-1-propyl-1H-indol-3-yl)-N-methylethanamine,2-(5-fluoro-4-(4-methylbenzyloxy)-1-propyl-1H-indol-3-yl)-N-methylethanamine,2-(5-fluoro-1-methyl-4-(2-methylphenethoxy)-1H-indol-3-yl)-N-methylethanamine,2-(5-fluoro-4-(4-(methylsulfonyl)benzyloxy)-1-propyl-1H-indol-3-yl)-N-methylethanamine,2-(4-(2-chlorophenethoxy)-5-fluoro-1-methyl-1H-indol-3-yl)-N-methylethanamine,2-(4-(2,4-dichlorobenzyloxy)-5-fluoro-1-methyl-1H-indol-3-yl)-N-methylethanamine,2-(4-(4-chlorobenzyloxy)-5-fluoro-1-propyl-1H-indol-3-yl)ethanamine2-(4-(4-chloro-3-(trifluoromethoxy)benzyloxy)-5-fluoro-1-methyl-1H-indol-3-yl)-N-methylethanamine,and2-(5-fluoro-1-methyl-4-(thiophen-2-ylmethoxy)-1H-indol-3-yl)-N,N-dimethylethanamine.

In another aspect, the invention is directed to a compound selected fromthe following formula:

wherein

g is 1, 2 or 3;

A¹ is optionally substituted C₃₋₆cycloalkylene, optionally substitutedheterocyclalkene, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted arylene, optionally substitutedheteroarylene, optionally substituted heterocycloalkylene or optionallysubstituted —C(O)—C₁₋₃ alkylene-, wherein arylene or heteroarylene areoptionally substituted with 1-3 substituents, each of which isindependently selected from the group consisting of halogen, C₃₋₈cycloalkyl, —OR^(d), C₁₋₈ haloalkoxy, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂ arylalkyl, —S(O)₀₋₂ heteroarylalkyl,—S(O)₀₋₂ C₁₋₈ cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂heterocycloalkylalkyl, —S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted —C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d), whereincycloalkylene and —C(O)—C₁₋₃ alkylene are optionally substituted withwith 1-3 substituents, each of which is independently selected from thegroup consisting of halogen, oxo, optionally substituted C₁₋₆ alkyl,—S(O)₀₋₂alkyl, —OR^(d) and —NR^(d)R^(d′), aryl or heteroaryl, and C₃-C₈cycloalkyl or 4-8 membered heterocyclyl. (e.g., wherein twosubstituents, together with the carbon to which they are attached, forma ring);

R¹ and R² are each independently selected from H, C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted arylalkyl, optionally substituted heteroarylalkyl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocycloalkyl or when taken together with the nitrogen atom to whichthey are attached, R¹ and R² form a 3-8 membered heterocyclic moiety orwhen taken together with the nitrogen atom to which they are attached R¹or R² and A form an optionally substituted 4-8 membered heterocyclyl orheteroaryl moiety;

R³ is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, halogen, orC(O)NR^(d)R^(d′);

W¹ is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted arylalkyl, optionally substituted cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted cycloalkylalkyl,optionally substituted heterocycloalkyl or optionally substitutedheteroarylalkyl;

R⁴ is selected from optionally substituted C₁₋₈ alkyl, optionallysubstituted C₁₋₈ heteroalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, —S(O)₂ alkyl,—S(O)₂ heteroalkyl, —S(O)₂ aryl, —S(O)₂ heteroaryl, —S(O)₂ cycloalkyl,—S(O)₂ heterocyclyl, —S(O)₂ heterocycloalkyl, —S(O)₂ arylalkyl, —S(O)₂heteroarylalkyl, —S(O)₂ cycloalkyalkyl, formyl, —OR^(d), —NR^(d)R^(d′),—C(O)OR^(a), —C(O)NR^(d)R^(d′), —S(O)₂NR^(d)R^(d′), C₃₋₈ cycloalkyl,heterocyclyl, cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl,arylalkyl, and heteroarylalkyl, wherein alkyl, cycloalkyl andheterocyclyl are optionally substituted with 1-3 substituents, halo,alkyl, haloalkyl, heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryland heteroaryl are optionally substituted with 1-3 substituents, each ofwhich is independently selected from the group consisting of halogen,alkyl, heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈haloalkoxy, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂-arylalkylaryl, —S(O)₀₋₂-heteroarylalkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —OR^(d), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), optionally substituted—C₁alkyl-C(O)NR^(e)R^(f), —C₁alkyl-O-aryl, —C₁alkyl-O-heteroaryl,—C₁alkyl-heterocyclyl, —C₁alkyl-cycloalkyl, cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d);

each R⁶ is independently selected from halo, C₁₋₈ alkyl, aryl,heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ arylalkyl, —S(O)₀₋₂ heteroarylalkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′) cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

R^(a), and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted cycloalkylalkyl and optionallysubstituted heterocycloalkyl; and

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety.

In another aspect, the invention is directed to a compound selected fromthe following formula:

wherein

g′ is 0, 1, 2 or 3;

Z is an optionally substituted heteroaryl or optionally substitutedheterocyclyl;

R¹ and R² are each independently selected from H, C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted arylalkyl, optionally substituted heteroarylalkyl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocycloalkyl or when taken together with the nitrogen atom to whichthey are attached, R¹ and R² form a 3-8 membered heterocyclic moiety orwhen taken together with the nitrogen atom to which they are attached R¹or R² and A form an optionally substituted 4-8 membered heterocyclyl orheteroaryl moiety;

R³ is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, halogen, orC(O)NR^(d)R^(d′);

A is optionally substituted C₁₋₄ alkylene, optionally substitutedcycloalkylene, optionally substituted arylene, optionally substitutedheteroarylene, optionally substituted heterocycloalkylene whereinarylene or heteroarylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, aryl, heteroaryl, C₃₋₈ cycloalkyl, —OR^(d), C₁₋₈haloalkoxy, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂ arylalkyl, —S(O)₀₋₂ heteroarylalkyl), —S(O)₀₋₂ cycloalkyl,—S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′) cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted —C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d), whereinalkylene and cycloalkylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, oxo, optionally substituted C₁₋₆ alkyl,—S(O)₀₋₂alkyl, —OR^(d) and —NR^(d)R^(d′), aryl or heteroaryl, and C₃-C₈cycloalkyl or 4-8 membered heterocyclyl (e.g., wherein two substituents,together with the carbon to which they are attached, form a ring);

R⁴ is selected from optionally substituted C₁₋₈ alkyl, optionallysubstituted C₁₋₈ heteroalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, —S(O)₂ alkyl,—S(O)₂ heteroalkyl, —S(O)₂ aryl, —S(O)₂ heteroaryl, —S(O)₂ cycloalkyl,—S(O)₂ heterocyclyl, —S(O)₂ heterocycloalkyl, —S(O)₂ arylalkyl, —S(O)₂heteroarylalkyl, —S(O)₂ cycloalkyalkyl, formyl, —OR^(d), —NR^(d)R^(d′),—C(O)OR^(a), —C(O)NR^(d)R^(d′), —S(O)₂NR^(d)R^(d′), C₃₋₈ cycloalkyl,heterocyclyl, cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl,arylalkyl, and heteroarylalkyl, wherein the alkyl, cycloalkyl andheterocyclyl are optionally substituted with 1-3 substituents, halo,alkyl, haloalkyl, heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryland herteroaryl are optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting of halogen,alkyl, heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈haloalkoxy, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂—C₁₋₄alkylaryl, —S(O)₀₋₂—C₁₋₄alkylheteroaryl,—OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b),—OR^(d), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl,—NR^(d)S(O)₂cycloalkyl, —NR^(d)S(O)₂heterocycloalkyl,—NR^(d)S(O)₂-arylalkyl, —NR^(d)S(O)₂-heteroarylalkyl,—NR^(d)S(O)₂-cycloalkylalkyl, —NR^(d)S(O)₂-heterocycloalkyl,—SO₂NR^(d)R^(d′), optionally substituted —C₁alkyl-C(O)NR^(e)R^(f),—C₁alkyl-O-aryl, —C₁alkyl-O-heteroaryl, —C₁alkyl-heterocyclyl,—C₁alkyl-cycloalkyl, cyano, nitro, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,—NR^(d)R^(d′), optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a),—C(O)NR^(d)R^(d′), and —C(O)OR^(d);

each R⁶ is independently selected from halo, C₁₋₈ alkyl, aryl,heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ arylalkyl, —S(O)₀₋₂ heteroarylalkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′) cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

R^(a), and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted cycloalkylalkyl and optionallysubstituted heterocycloalkyl, or when taken together with the nitrogenatom to which they are attached, R^(a) and R^(b) form a 4-8 memberedheterocyclic moiety; and

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety.

In some embodiments, R¹ and R² are each independently selected from H,C₁₋₈ alkyl, and optionally substituted aryl.

In some embodiments, A is selected from optionally substituted C₁₋₄alkylene, wherein the C₁₋₄ alkylene is optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, hydroxyl, optionally substituted C₁₋₆ alkyl, C₁₋₈alkoxy, —SO₂ alkyl, —NR^(d)R^(d′), aryl or heteroaryl, and C₃-C₈cycloalkyl or 4-8 membered heterocyclyl (e.g., wherein two substituents,together with the carbon to which they are attached, form a ring)

In some embodiments, R³ is selected from H, halogen, and optionallysubstituted C₁₋₈ alkyl.

In some embodiments, R⁴ is selected from C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, aralalkyl,heteroaralalkyl, —S(O)₂ alkyl, —S(O)₂ arylalkyl, —S(O)₂ heteroarylalkyl,—S(O)₂ aryl, —S(O)₂ cycloalkyl, —S(O)₂ heterocycloalkyl, —S(O)₂heterocycloalkylalkyl, —S(O)₂ cycloalkylalkyl, and —S(O)₂ heteroaryl.

In some embodiments, R⁴ is optionally substituted C₁₋₈ alkyl.

In some embodiments,

is optionally substituted

In some embodiments,

In some embodiments, the compound is selected from

In some embodiments, the compound is2-(7-propyl-3,7-dihydro-2H-[1,4]dioxino[2,3-e]indol-9-yl)ethanamine.

In another aspect, the invention is directed to a compound selected fromthe following formula:

wherein

R¹ and R² are each independently selected from H, C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted arylalkyl, optionally substituted heteroarylalkyl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocycloalkyl or when taken together with the nitrogen atom to whichthey are attached, R¹ and R² form a 3-8 membered heterocyclic moiety orwhen taken together with the nitrogen atom to which they are attached R¹or R² and A form an optionally substituted 4-8 membered heterocyclyl orheteroaryl moiety;

R³ is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, halogen, orC(O)NR^(d)R^(d′);

W² is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted arylalkyl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, optionallysubstituted heteroarylalkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocycloalkyl, or —C(O)NR^(d)R^(d′);

A is optionally substituted C₁₋₄ alkylene, optionally substitutedcycloalkylene, optionally substituted arylene, optionally substitutedheteroarylene, optionally substituted heterocycloalkylene whereinarylene or heteroarylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, optionally substituted aryl, optionallysubstituted heteroaryl, C₃₋₈ cycloalkyl, —OR^(d), C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂arylalkyl, —S(O)₀₋₂ heteroarylalkyl), —S(O)₀₋₂ cycloalkyl, —S(O)₀₋₂heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d), whereinalkylene and cycloalkylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, oxo, optionally substituted C₁₋₆ alkyl,—S(O)₀₋₂alkyl, —OR^(d) and —NR^(d)R^(d′), aryl or heteroaryl, and C₃-C₈cycloalkyl or 4-8 membered heterocyclyl (e.g., wherein two substituents,together with the carbon to which they are attached, form a ring);

R⁴ is selected from optionally substituted C₁₋₈ alkyl, optionallysubstituted C₁₋₈ heteroalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, —S(O)₂ alkyl,—S(O)₂ heteroalkyl, —S(O)₂ aryl, —S(O)₂ heteroaryl, —S(O)₂ cycloalkyl,—S(O)₂ heterocyclyl, —S(O)₂ heterocycloalkyl, —S(O)₂ arylalkyl, —S(O)₂heteroarylalkyl, —S(O)₂ cycloalkyalkyl, formyl, —OR^(d), —NR^(d)R^(d′),—C(O)OR^(a), —C(O)NR^(d)R^(d′), —S(O)₂NR^(d)R^(d′), C₃₋₈ cycloalkyl,heterocyclyl, cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl,arylalkyl, and heteroarylalkyl, wherein the alkyl, cycloalkyl andheterocyclyl are optionally substituted with 1-3 substituents, halo,alkyl, haloalkyl, heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryland herteroaryl are optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting of halogen,alkyl, heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈haloalkoxy, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂-arylalkyl, —S(O)₀₋₂-heteroarylalkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —OR^(d), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), optionally substituted—C₁alkyl-C(O)NR^(e)R^(f), —C₁alkyl-O-aryl, —C₁alkyl-O-heteroaryl,—C₁alkyl-heterocyclyl, —C₁alkyl-cycloalkyl, cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d);

each R^(6′) is independently selected from hydrogen, halo, C₁₋₈ alkyl,aryl, heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ arylalkyl, —S(O)₀₋₂ heteroarylalkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′),and —C(O)OR^(d), wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

R^(6″) is halo, optionally substituted C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, heteroalkyl, C₃₋₈cycloalkyl, optionally substituted heterocyclyl, aralalkyl, optionallysubstituted heteroarylalkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocycloalkyl, —SH, —OR^(d), C₁₋₈ haloalkoxy,C₁₋₈ haloalkyl, alkyl-C(O)NR^(e)R^(f), alkyl-C(O)-heterocyclyl, —S(O)₀₋₂C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂ arylalkyl,—S(O)₀₋₂ heteroarylalkyl, —S(O)₀₋₂ cycloalkyl, —S(O)₀₋₂heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d),—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, -alkyl-OH, -alkyl-OR^(d), -alkyl-NH₂,-alkyl-NR^(d)R^(d′), -alkynyl-OH, -alkynyl-OR^(d), -alkenyl-OH,-alkenyl-OR^(d), -alkynyl-COOR^(d) and -alkynyl-COOR^(d),-alkenyl-COOR^(d) and -alkenyl-COOR^(d), -alkynyl-CONR^(d′)R^(d),-alkynyl-CO, NR^(d′)R^(d), -alkenyl-CONR^(d′)R^(d) and-alkenyl-CONR^(d′)R^(d), alkynyl-SO₂NR^(d)R^(d′), NR^(d)-aryl,NR^(d)-heteroaryl, cyano, nitro, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,—NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′) optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d), whereinalkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl are optionallysubstituted, wherein R^(e) and R^(f) are selected from the same groupslisted for R¹ and R², respectively;

R^(a), and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted cycloalkylalkyl and optionallysubstituted heterocycloalkyl;

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety.

In some embodiments, R¹ and R² are each independently selected from H,optionally substituted C₁₋₈ alkyl, and optionally substituted aryl.

In some embodiments, A is C₁₋₄ alkylene, wherein the C₁₋₄ alkylene isoptionally substituted with 1-3 substituents, each of which isindependently selected from the group consisting of halogen, hydroxyl,optionally substituted C₁₋₆ alkyl, C₁₋₈ alkoxy, —SO₂ alkyl, and—NR^(d)R^(d′).

In some embodiments, R³ is selected from H, and optionally substitutedC₁₋₈ alkyl.

In some embodiments, R⁴ is selected from optionally substituted C₁₋₈alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —S(O)₂ alkyl,—S(O)₂ arylalkyl, —S(O)₂ heteroarylalkyl, —S(O)₂ aryl, —S(O)₂cycloalkyl, —S(O)₂ heterocycloalkyl, —S(O)₂ heterocycloalkylalkyl,—S(O)₂ cycloalkylalkyl, and —S(O)₂ heteroaryl.

In some embodiments, W² is hydrogen, or C₁₋₈ alkyl optionallysubstituted with —OR^(d), —NR^(d)R^(d′), —C(O)NR^(d)R^(d′).

In some embodiments, W² is optionally substituted C₁₋₈ alkyl.

In some embodiments, R^(6′) is selected from hydrogen, halogen and C₁₋₈alkyl.

In some embodiments, R^(6″) is optionally substituted aryl, optionallysubstituted heteroaryl, heterocyclyl, cycloalkyl, —OR^(d), C₂₋₈ alkynyl,—NH-aryl, —NH-heteroaryl, —NH— alkyl, —NR^(d)-aryl, —NR^(d)-heteroaryl,—NR^(d)-arylalkyl, —NR^(d)-heteroarylalkyl, —NR^(d)-heterocyclyl,—NR^(d)-heterocyclylalkyl, —NR^(d)-heterocyclyl, —NR^(d)-cyclylalkyl,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂arylalkyl, —S(O)₀₋₂ heteroarylalkyl, —S(O)₀₋₂ cycloalkyl, —S(O)₀₋₂heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —NR^(d)-alkyl, —C₁alkyl-aryl, —C₁alkyl-heteroaryl,heterocyclyl, —C₁alkyl-cycloalkyl, —C₁alkyl-NR^(d)-alkyl, aryloxy, andheteroaryloxy.

In some embodiments, R^(6″) is selected from optionally substitutedaryl, optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted heteroaryl, optionallysubstituted cycloalkyl, optionally substituted aryloxy, optionallysubstituted heteroaryloxy, —NH-aryl, C₁₋₈ alkynoxy, andalkyl-C(O)NR^(e)R^(f), wherein R^(e) and R^(f) are selected from thesame groups listed for R¹ and R², respectively.

In some embodiments, R^(6″) is hydroxyl C₂₋₈ alkynyl.

In some embodiments, R⁶″ is —SO₂aryl, —SO₂heteroaryl,—C₁alkylCONR^(d)R^(d′), -alkynyl-OR^(d), -alkyl-OR^(d),-alkylNR^(d)R^(d′), arylalkyl, heteroarylalkyl, or cycloalkylalkyl.

In some embodiments, the compound is selected from

Optionally, R6″ is S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ arylalkyl, —S(O)₀₋₂ heteroarylalkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,or —S(O)₀₋₂ cycloalkylalkyl. Optionally, R6″ is alkyl-C(O)NR^(e)R^(f),wherein R^(e) and R^(f) are selected from the same groups listed for R¹and R², respectively.

In some embodiments, R^(6″) is optionally substituted aryl, heteroaryl,heterocyclyl, cycloalkyl, —OR^(d), C₂₋₈alkynyl, —NH-aryl, or—NH-heteroaryl.

In some embodiments, the compound is selected from the group consistingof2-(7-fluoro-4-methoxy-1-methyl-5-phenyl-1H-indol-3-yl)-N,N-dimethylethanamine,2-(4-methoxy-1-methyl-7-(pyridin-3-yl)-1H-indol-3-yl)-N,N-dimethylethanamine,2-(4-methoxy-1-methyl-7-phenyl-1H-indol-3-yl)-N,N-dimethylethanamine,2-(4-methoxy-1-methyl-7-(thiophen-3-yl)-1H-indol-3-yl)-N,N-dimethylethanamine,2-(4-methoxy-1-methyl-7-(thiophen-2-yl)-1H-indol-3-yl)-N,N-dimethylethanamine,2-(7-(furan-2-yl)-4-methoxy-1-methyl-1H-indol-3-yl)-N,N-dimethylethanamine,2-(7-(furan-3-yl)-4-methoxy-1-methyl-1H-indol-3-yl)-N,N-dimethylethanamine,2-(4-methoxy-1-methyl-7-(1H-pyrrol-2-yl)-1H-indol-3-yl)-N,N-dimethylethanamine,3-(3-(2-(dimethylamino)ethyl)-4-methoxy-1-methyl-1H-indol-7-yl)prop-2-yn-1-ol,3-(2-(dimethylamino)ethyl)-4-methoxy-1-methyl-N-phenyl-1H-indol-7-amine,(E)-methyl3-(3-(2-(dimethylamino)ethyl)-4-methoxy-1-methyl-1H-indol-7-yl)acrylate,3-(3-(2-(dimethylamino)ethyl)-1-ethyl-7-fluoro-4-methoxy-1H-indol-5-yl)propan-1-ol,2-(1-ethyl-4-methoxy-6-phenyl-1H-indol-3-yl)-N,N-dimethylethanamine,3-(3-(2-(dimethylamino)ethyl)-1-ethyl-7-fluoro-4-methoxy-1H-indol-5-yl)propan-1-amine,2-(5-(2-(1H-benzo[d]imidazol-2-yl)ethyl)-1-ethyl-7-fluoro-4-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine.2-(4-methoxy-1-methyl-7-(phenylsulfonyl)-1H-indol-3-yl)-N,N-dimethylethanamine,2-(7-fluoro-4-methoxy-1-methyl-5-phenyl-1H-indol-3-yl)-N-methylethanamine,3-(3-(2-(dimethylamino)ethyl)-4-methoxy-1-methyl-1H-indol-7-yl)propan-1-ol,2-(7-fluoro-4-methoxy-1-methyl-5-phenethyl-1H-indol-3-yl)-N-methylethanamine,and2-(5-(2-cyclohexylethyl)-7-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)-N-methylethanamine.

In another aspect, the invention is directed to the following formula:

wherein

g is 1, 2 or 3;

R^(1a) is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted arylalkyl, optionally substituted heteroarylalkyl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocycloalkyl;

Q is selected from aryl, heteroaryl, arylalkyl, heterocycloalkyl,heteroarylalkyl, alkyl-C(O)NR^(e)R^(f), alkyl-C(O)-heterocyclyl,heterocycloalkyl-alkyl, cycloalkyl, cycloalkylaryl, cycloalkylalkyl,arylheteroalkyl, and heteroarylheteroalkyl, wherein Q is optionallysubstituted with 1-3 substituents, each of which is independentlyselected from the group consisting of optionally substituted—C₁₋₆heteroalkyl, halogen, C₃₋₈ cycloalkyl, —OR^(d), C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂arylalkyl, —S(O)₀₋₂ heteroarylalkyl), —S(O)₀₋₂ cycloalkyl, —S(O)₀₋₂heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″)—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆ haloalkyl, —NR^(d)R^(d′), aryl,heteroaryl, heterocyclyl, -alkyl-OR^(d), optionally substituted —C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O), wherein R^(e) andR^(f) are selected from the same groups as R¹ and R², respectively;

R³ is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, halogen, orC(O)NR^(d)R^(d′);

W² is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted arylalkyl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, optionallysubstituted heteroarylalkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocycloalkyl, or —C(O)NR^(d)R^(d′);

A is optionally substituted C₁₋₄ alkylene, optionally substitutedcycloalkylene, optionally substituted arylene, optionally substitutedheteroarylene, wherein arylene or heteroarylene are optionallysubstituted with 1-3 substituents, each of which is independentlyselected from the group consisting of halogen, optionally substitutedaryl, optionally substituted heteroaryl, C₃₋₈ cycloalkyl, —OR^(d), C₁₋₈haloalkoxy, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂ arylalkyl, —S(O)₀₋₂ heteroarylalkyl), —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂—C₁₋₄alkyl-heteroaryl, —NR^(d)S(O)₂—C₁₋₄alkyl-cycloalkyl,—NR^(d)S(O)₂—C₁₋₄alkyl-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substitutedC₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d),wherein alkylene and cycloalkylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, oxo, optionally substituted C₁₋₆ alkyl,—S(O)₀₋₂alkyl, —OR^(d) and —NR^(d)R^(d′), aryl or heteroaryl, and C₃-C₈cycloalkyl or 4-8 membered heterocyclyl (e.g., wherein two substituents,together with the carbon to which they are attached, form a ring);

R⁴ is selected from optionally substituted C₁₋₈ alkyl, optionallysubstituted C₁₋₈ heteroalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, —S(O)₂ alkyl,—S(O)₂ heteroalkyl, —S(O)₂ aryl, —S(O)₂ heteroaryl, —S(O)₂ cycloalkyl,—S(O)₂ heterocyclyl, —S(O)₂ heterocycloalkyl, —S(O)₂ arylalkyl, —S(O)₂heteroarylalkyl, —S(O)₂ cycloalkyalkyl, formyl, —OR^(d), —NR^(d)R^(d′),—C(O)OR^(a), —C(O)NR^(d)R^(d′), —S(O)₂NR^(d)R^(d′), C₃₋₈ cycloalkyl,heterocyclyl, cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl,arylalkyl, and heteroarylalkyl, wherein the alkyl, cycloalkyl andheterocyclyl are optionally substituted with 1-3 substituents, halo,alkyl, haloalkyl, heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryland herteroaryl are optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting of halogen,alkyl, heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈haloalkoxy, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂-arylalkyl, —S(O)₀₋₂-heteroarylalkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —OR^(d), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), optionally substituted—C₁alkyl-C(O)NR^(e)R^(f), —C₁alkyl-O-aryl, —C₁alkyl-O-heteroaryl,—C₁alkyl-heterocyclyl, —C₁alkyl-cycloalkyl, cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d);

each R⁶ is independently selected from halo, C₁₋₈ alkyl, aryl,heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ arylalkyl, —S(O)₀₋₂ heteroarylalkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′) cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

R^(a), and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted cycloalkylalkyl and optionallysubstituted heterocycloalkyl;

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety.

In some embodiments, the compound isN-(2-(1-ethyl-7-fluoro-4-methoxy-1H-indol-3-yl)ethyl)aniline or1-ethyl-7-fluoro-3-(2-(phenylamino)ethyl)-1H-indol-4-ol.

In some embodiments, R^(1a) is selected from H, optionally substitutedC₁₋₈ alkyl, and optionally substituted aryl.

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting of halogen,hydroxyl, optionally substituted C₁₋₆ alkyl, C₁₋₈ alkoxy, —SO₂ alkyl,and —NR^(d)R^(d′).

In some embodiments, R³ is selected from hydrogen, halogen, andoptionally substituted C₁₋₈ alkyl.

In some embodiments, R⁴ is selected from optionally substituted C₁₋₈alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —S(O)₂ alkyl,—S(O)₂ arylalkyl, —S(O)₂ heteroarylalkyl, —S(O)₂ aryl, —S(O)₂cycloalkyl, —S(O)₂ heterocycloalkyl, —S(O)₂ heterocycloalkylalkyl,—S(O)₂ cycloalkylalkyl and —S(O)₂ heteroaryl.

In some embodiments, W² is H, or C₁₋₈ alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′), —C(O)NR^(d)R^(d′).

In some embodiments, Q is selected from aryl, heteroaryl, arylalkyl,heterocycloalkyl, heteroarylalkyl, wherein Q is optionally substitutedwith 1-3 substituents, each of which is independently selected from thegroup consisting of halogen, C₃₋₈ cycloalkyl, —OR^(d), C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂arylalkyl, —S(O)₀₋₂ heteroarylalkyl), —S(O)₀₋₂ cycloalkyl, —S(O)₀₋₂heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted —C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O).

In some embodiments, Q is optionally substituted aryl, optionallysubstituted heteroarylalkyl, or optionally substituted arylalkyl.

In some embodiments, Q is optionally substituted arylalkyl or optionallysubstituted six-membered heteroarylalkyl wherein the substitution is atthe ortho or para position.

In some embodiments, R⁶ is selected from halogen, C₁₋₈ alkyl, hydroxyl,—C₁₋₈ fluoroalkyl, amino, and —NR^(d)R^(d′).

In some embodiments, the compound is selected from

wherein Ar is optionally substituted aryl or optionally substitutedheteroaryl, and heterocyclyl is optionally substituted 4-8-memberheterocycle. Optionally, Ar or the heterocyclyl is substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, C₃₋₈ cycloalkyl, —OR^(d), C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂arylalkyl, —S(O)₀₋₂ heteroarylalkyl), —S(O)₀₋₂ cycloalkyl, —S(O)₀₋₂heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted —C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O).

In some embodiments, the compound is selected fromN-(2-(1-ethyl-7-fluoro-4-methoxy-1H-indol-3-yl)ethyl)aniline,

1-ethyl-7-fluoro-3-(2-(phenylamino)ethyl)-1H-indol-4-ol,N-benzyl-2-(1-ethyl-7-fluoro-4-methoxy-1H-indol-3-yl)ethanamine,3-(2-(benzylamino)ethyl)-1-ethyl-6-fluoro-1H-indol-4-ol,2-(4-(benzyloxy)-1-ethyl-6-fluoro-1H-indol-3-yl)-N-(3-(trifluoromethyl)phenethyl)ethanamine,1-ethyl-6-fluoro-3-(2-(3-(trifluoromethyl)phenethylamino)ethyl)-1H-indol-4-ol,1-ethyl-6-fluoro-3-(2-(2-phenylpropylamino)ethyl)-1H-indol-4-ol,N-benzyl-2-(4-(benzyloxy)-1-ethyl-6-fluoro-1H-indol-3-yl)ethanamine,N-benzyl-2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)ethanamine,N-(2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)ethyl)-2,3-dihydro-1H-inden-2-amine,2-(4-(benzyloxy)-1-ethyl-6-fluoro-1H-indol-3-yl)-N-phenethylethanamine,N-(2-chlorobenzyl)-2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)ethanamine,N-(benzo[d][1,3]dioxol-5-ylmethyl)-2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)ethanamine,N-(2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)ethyl)-2,3-dihydro-H-inden-1-amine1-ethyl-6-fluoro-3-(2-(phenethylamino)ethyl)-1H-indol-4-ol,2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)-N-(3-methylbenzyl)ethanamine,N-benzyl-2-(4-(benzyloxy)-1-ethyl-6-fluoro-1H-indol-3-yl)-N-methylethanamine,2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)-N-(2-(trifluoromethyl)benzyl)ethanamine,2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)-N-(3-(trifluoromethyl)benzyl)ethanamine,2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)-N-phenethylethanamine,2-(1-ethyl-7-fluoro-4-methoxy-1H-indol-3-yl)-N-phenethylethanamine,2-(benzo[d][1,3]dioxol-5-yl)-N-(2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)ethyl)ethanamine,N-benzyl-2-(1-ethyl-6-fluoro-4-methoxy-1H-indol-3-yl)ethanamine,2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)-N-(2-(pyridin-2-yl)ethyl)ethanamine,2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)-N-(thiophen-2-ylmethyl)ethanamine,2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)-N-(thiophen-2-ylmethyl)ethanamine,N-benzyl-2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethanamine,2-(1-ethyl-6-fluoro-4-methoxy-1H-indol-3-yl)-N-(2-(1-ethyl-6-fluoro-4-methoxy-1H-indol-3-yl)ethyl)-N-methylethanamine,2-(4-(benzyloxy)-1-ethyl-6-fluoro-1H-indol-3-yl)-N-(3-(trifluoromethyl)benzyl)ethanamine,2-(4-(benzyloxy)-1-ethyl-6-fluoro-1H-indol-3-yl)-N-(3-chlorobenzyl)ethanamine,2-(1-ethyl-7-fluoro-4-methoxy-1H-indol-3-yl)-N-(1-phenylethyl)ethanamine,2-(1-ethyl-7-fluoro-4-methoxy-1H-indol-3-yl)-N-(2-methylbenzyl)ethanamine,N-(2-chlorobenzyl)-2-(1-ethyl-7-fluoro-4-methoxy-1H-indol-3-yl)ethanamine,N-(3,4-dimethoxybenzyl)-2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethanamine,3-(2-(benzhydrylamino)ethyl)-1-ethyl-6-fluoro-1H-indol-4-ol,2-(2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethylamino)-2-phenylethanol,2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)-N-(1-phenylethyl)ethanamine,3-(2-(3-chlorobenzylamino)ethyl)-1-ethyl-6-fluoro-1H-indol-4-ol,1-ethyl-6-fluoro-3-(2-(3-(trifluoromethyl)benzylamino)ethyl)-1H-indol-4-ol,N-(2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethyl)-4-phenylbutan-1-amine,3-(2-(benzylamino)ethyl)-5-fluoro-1-methyl-1H-indol-4-ol,(S)-N-(2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine,(S)-N-(2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine,N-(2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethyl)-3-(4-methylpiperazin-1-yl)aniline,5-fluoro-3-(2-((6-methylpyridin-2-yl)methylamino)ethyl)-1-propyl-1H-indol-4-ol,and5-fluoro-1-methyl-3-(2-((6-methylpyridin-2-yl)methylamino)ethyl)-1H-indol-4-ol.

In another aspect, the invention is directed to a compound of formula:

wherein

L is a bond, —SO₂—, or optionally substituted C₁₋₃ alkylene;

M is —C(O)NR^(e)R^(f), optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted arylalkyl, optionallysubstituted alkyl amido, optionally substituted alkoxy, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocycloalkyl,optionally substituted heteroarylkyl, optionally substituted arylalkoxylene, optionally substituted heteroaryl alkoxylene, optionallysubstituted heterocyclyl alkoxylene, or optionally substitutedcycloalkyl alkoxylene wherein R^(e) and R^(f) selected from the samegroups as R¹ and R², respectively;

R¹ and R² are each independently selected from H, C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted arylalkyl, optionally substituted heteroarylalkyl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocycloalkyl or when taken together with the nitrogen atom to whichthey are attached, R¹ and R² form a 3-8 membered heterocyclic moiety orwhen taken together with the nitrogen atom to which they are attached R¹or R² and A form an optionally substituted 4-8 membered heterocyclyl orheteroaryl moiety;

R³ is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, halogen, orC(O)NR^(d)R^(d′);

W² is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted arylalkyl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, optionallysubstituted heteroarylalkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocycloalkyl, or —C(O)NR^(d)R^(d′);

A is optionally substituted C₁₋₄ alkylene, optionally substitutedcycloalkylene, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted arylene, optionally substitutedheteroarylene, optionally substituted heterocycloalkylene whereinarylene or heteroarylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, C₃₋₈ cyclo optionally substituted aryl,optionally substituted heteroaryl, alkyl, —OR^(d), C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂arylalkyl, —S(O)₀₋₂ heteroarylalkyl), —S(O)₀₋₂ cycloalkyl, —S(O)₀₋₂heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′) optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d), whereinalkylene and cycloalkylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, oxo, optionally substituted C₁₋₆ alkyl,—S(O)₀₋₂alkyl, —OR^(d) and —NR^(d)R^(d′), aryl or heteroaryl, and C₃-C₈cycloalkyl or 4-8 membered heterocyclyl (e.g., wherein two substituents,together with the carbon to which they are attached, form a ring);

each R⁶ is independently selected from halo, C₁₋₈ alkyl, aryl,heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ arylalkyl, —S(O)₀₋₂ heteroarylalkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

g is 1, 2, or 3;

R^(a), and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted cycloalkylalkyl and optionallysubstituted heterocycloalkyl; and

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety.

In some embodiments, R¹ and R² are each independently selected from H,C₁₋₈ alkyl, and optionally substituted aryl.

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting of halogen(e.g., fluorine), hydroxyl, optionally substituted C₁₋₆ alkyl, C₁₋₈alkoxy, —SO₂ alkyl, and —NR^(d)R^(d′).

In some embodiments, R³ is selected from H, and optionally substitutedC₁₋₈ alkyl.

In some embodiments, L is a bond, or optionally substituted C₁₋₃alkylene.

In some embodiments, L is a bond.

In some embodiments, L is SO₂.

In some embodiments, M is optionally substituted with 1-3 substituents,each of which is independently selected from the group consisting ofhalogen, C₃₋₈ cycloalkyl, —OR^(d), C₁₋₈ haloalkoxy, —S(O)₀₋₂ C₁₋₈ alkyl,—S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂ arylalkyl, —S(O)₀₋₂heteroarylalkyl), —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′) optionally substituted —C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d′).

In some embodiments, M is arylalkyl or heteroarylalkyl optionallysubstituted on the alkyl moiety.

In some embodiments, M is optionally substituted heteroarylalkyl.

In some embodiments, M is optionally substituted alkyl amido.

In some embodiments, M is optionally substituted alkoxy.

In some embodiments, M is optionally substituted arylalkoxylene,optionally substituted heteroarylalkoxylene, optionally substitutedcycloalkylalkoxylene, or optionally substitutedheterocycloalkylalkoxylene.

In some embodiments, W² is C₁₋₈ alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′)—C(O)NR^(d)R^(d′).

In some embodiments, each R⁶ is selected from halogen, optionallysubstituted C₁₋₈ alkyl, hydroxyl, —C₁₋₈ fluoroalkyl, C₁₋₈ haloalkoxy,and —NR^(d)R^(d′).

In some embodiments, the compound is selected from:

-   2-(6-fluoro-4-methoxy-1-(phenylsulfonyl)-1H-indol-3-yl)-N,N-dimethylethanamine,-   2-(1-benzyl-4-(benzyloxy)-7-fluoro-1H-indol-3-yl)-N,N-dimethylethanamine,-   2-(6-fluoro-4-methoxy-1-(pyrimidin-2-yl)-1H-indol-3-yl)-N,N-dimethylethanamine,-   2-(4-(benzyloxy)-7-fluoro-1-(4-methoxybenzyl)-1H-indol-3-yl)-N,N-dimethylethanamine,-   3-(2-(dimethylamino)ethyl)-7-fluoro-1-(4-methoxybenzyl)-1H-indol-4-ol,-   2-(4-(benzyloxy)-7-fluoro-1-(pyridin-2-ylmethyl)-1H-indol-3-yl)-N,N-dimethylethanamine,-   3-(2-(dimethylamino)ethyl)-7-fluoro-1-(pyridin-2-ylmethyl)-1H-indol-4-ol,-   2-(4-(benzyloxy)-7-fluoro-1-(naphthalen-2-ylmethyl)-1H-indol-3-yl)-N,N-dimethylethanamine,-   3-(2-(dimethylamino)ethyl)-7-fluoro-1-(naphthalen-2-ylmethyl)-1H-indol-4-ol,-   2-(4-(benzyloxy)-7-fluoro-1-(thiophen-2-ylmethyl)-1H-indol-3-yl)-N,N-dimethylethanamine,    and-   1-benzyl-3-(2-(dimethylamino)ethyl)-7-fluoro-1H-indol-4-ol.

In some embodiments, M is

C(O)NR^(e)R^(f),

wherein R^(e) and R^(f) selected from the same groups as R¹ and R²,respectively. Optionally, L is —CH₂—.

In some embodiments, M is —C(O)NR^(e)R^(f), aryl, heteroaryl,arylalkoxylene, or heteroarylalkoxylene, wherein R^(e) and R^(f)selected from the same groups as R¹ and R², respectively.

In some embodiments, M is heterocyclyl and L is optionally substitutedC₁alkyl.

In some embodiments, L is C₁-alkyl and M is —C(O)NR^(e)R^(f), aryl,heteroaryl, or heterocyclyl.

In some embodiments, L is C₂-C₄-alkyl and M is —O-aryl, —NR^(e)-aryl,—O-heteroaryl, or —NR^(e)-heteroaryl.

In some embodiments, L is C₂-C₄-alkyl and M is optionally substitutedaryl alkoxylene, optionally substituted heteroaryl alkoxylene.

In some embodiments, the compound is selected from

In another aspect, the invention is directed to a compound of formula:

wherein

g is 1, 2 or 3;

R³ is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, halogen, orC(O)NR^(d)R^(d′);

W² is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted arylalkyl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, optionallysubstituted heteroarylalkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocycloalkyl, or —C(O)NR^(d)R^(d′);

Q′ is selected from is aryl, heteroaryl, arylalkyl, heterocycloalkyl orheteroarylalkyl, wherein Q′ is optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, C₃₋₈ cycloalkyl, —OR^(d), C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂arylalkyl, —S(O)₀₋₂ heteroarylalkyl), —S(O)₀₋₂ cycloalkyl, —S(O)₀₋₂heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted —C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O);

R⁴ is selected from optionally substituted C₁₋₈ alkyl, C₁₋₈ heteroalkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, —S(O)₂ alkyl, —S(O)₂ heteroalkyl, —S(O)₂aryl, —S(O)₂ heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂ heterocyclyl, —S(O)₂heterocycloalkyl, —S(O)₂ arylalkyl, —S(O)₂ heteroarylalkyl, —S(O)₂cycloalkyalkyl, formyl, —OR^(d), —NR^(d)R^(d′), —C(O)OR^(a),—C(O)NR^(d)R^(d′) S(O)₂NR^(d)R^(d′), C₃₋₈ cycloalkyl, heterocyclyl,cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl, arylalkyl, andheteroarylalkyl, wherein the alkyl, cycloalkyl and heterocyclyl areoptionally substituted with 1-3 substituents, halo, alkyl, haloalkyl,heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryl and herteroarylare optionally substituted with 1-3 substituents, each of which isindependently selected from the group consisting of halogen, alkyl,heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂-arylalkyl, —S(O)₀₋₂-heteroarylalkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —OR^(d), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), optionally substituted—C₁alkyl-C(O)NR^(e)R^(f), —C₁alkyl-O-aryl, —C₁alkyl-O-heteroaryl,—C₁alkyl-heterocyclyl, —C₁alkyl-cycloalkyl, cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d);

each R⁶ is independently selected from halo, C₁₋₈ alkyl, aryl,heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ arylalkyl, —S(O)₀₋₂ heteroarylalkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

R^(a), and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted cycloalkylalkyl and optionallysubstituted heterocycloalkyl;

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety.

In another aspect, the invention is directed to a compound of formula:

wherein

g is 1, 2 or 3;

is an optionally substituted N-containing heterocyclyl or optionallysubstituted N-containing heteroaryl;

A² is a bond or and optionally substituted C₁₋₄ alkylene;

R³ is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, halogen, orC(O)NR^(d)R^(d′);

W² is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted arylalkyl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, optionallysubstituted heteroarylalkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocycloalkyl, or —C(O)NR^(d)R^(d′);

R⁴ is selected from optionally substituted C₁₋₈ alkyl, optionallysubstituted C₁₋₈ heteroalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, —S(O)₂ alkyl,—S(O)₂ heteroalkyl, —S(O)₂ aryl, —S(O)₂ heteroaryl, —S(O)₂ cycloalkyl,—S(O)₂ heterocyclyl, —S(O)₂ heterocycloalkyl, —S(O)₂ arylalkyl, —S(O)₂heteroarylalkyl, —S(O)₂ cycloalkyalkyl, formyl, —OR^(d), —NR^(d)R^(d′),—C(O)OR^(a), —C(O)NR^(d)R^(d′), —S(O)₂NR^(d)R^(d′), C₃₋₈ cycloalkyl,heterocyclyl, cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl,arylalkyl, and heteroarylalkyl, wherein the alkyl, cycloalkyl andheterocyclyl are optionally substituted with 1-3 substituents, halo,alkyl, haloalkyl, heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryland herteroaryl are optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting of halogen,alkyl, heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈haloalkoxy, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂-arylalkyl, —S(O)₀₋₂-heteroarylalkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —OR^(d), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), optionally substituted—C₁alkyl-C(O)NR^(e)R^(f), —C₁alkyl-O-aryl, —C₁alkyl-O-heteroaryl,—C₁alkyl-heterocyclyl, —C₁alkyl-cycloalkyl, cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d);

each R⁶ is independently selected from halo, C₁₋₈ alkyl, aryl,heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ arylalkyl, —S(O)₀₋₂ heteroarylalkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′) cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

R^(a) and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted cycloalkylalkyl and optionallysubstituted heterocycloalkyl, or when taken together with the nitrogenatom to which they are attached, R^(a) and R^(b) form a 4-8 memberedheterocyclic moiety;

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety.

In some embodiments, A² is optionally substituted C₁₋₄ alkylene.

In some embodiments, R³ is selected from H, and optionally substitutedC₁₋₈ alkyl.

In some embodiments, R⁴ is selected from optionally substituted C₁₋₈alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —S(O)₂ alkyl,—S(O)₂ arylalkyl, —S(O)₂ heteroarylalkyl, —S(O)₂ aryl, —S(O)₂heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂ heterocycloalkyl, —S(O)₂heterocycloalkylalkyl, and —S(O)₂ cycloalkylalkyl.

In some embodiments, W² is C₁₋₈ alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′), —C(O)NR^(d)R^(d′).

In some embodiments, g is 1.

In some embodiments, each R⁶ is selected from halogen, optionallysubstituted C₁₋₈ alkyl, hydroxyl, —C₁₋₈ fluoroalkyl, C₁₋₈ haloalkoxy,and —NR^(d)R^(d′).

In some embodiments, the compound is selected from

wherein

is an optionally substituted N-containing heterocyclyl or optionallysubstituted N-containing heteroaryl.

In some embodiments,

is 3-14 membered (e.g., 4-14 membered, or 5-8 membered) heteroaryl orheterocyclyl.

In some embodiments,

is an N-containing heterocyclyl optionally substituted with 1-3substituents independently selected from the groupconsisting of aryl, heteroaryl, alkyl, arylalkyl, and heteroarylalkyl.

In some embodiments,

is optionally substituted:

In some embodiments,

In some embodiments,

is an optionally substituted

Sometimes,

is optionally substituted with 1-3 substituents independently selectedfrom the group consisting of halogen, alkyl, and haloalkyl.

In some embodiments, the compound is

wherein

is a heterocycle.

In some embodiments, the compound is selected from4-(2-(7-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethyl)morpholine,

1-ethyl-6-fluoro-3-(2-morpholinoethyl)-1H-indol-4-ol,1-ethyl-6-fluoro-3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol,7-fluoro-4-methoxy-1-methyl-3-(2-(pyrrolidin-1-yl)ethyl)-1H-indole,4-(benzyloxy)-1-ethyl-6-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole,3-(2-(1,4-oxazepan-4-yl)ethyl)-1-ethyl-6-fluoro-H-indol-4-ol,3-(2-((2S,6R)-2,6-dimethylmorpholino)ethyl)-1-ethyl-6-fluoro-1H-indol-4-ol,3-(2-(3,3-difluoropyrrolidin-1-yl)ethyl)-1-ethyl-6-fluoro-1H-indol-4-ol,1-ethyl-6-fluoro-3-(piperidin-3-yl)-1H-indol-4-ol,1-ethyl-6-fluoro-3-(1-methylpiperidin-3-yl)-1H-indol-4-ol,1-ethyl-6-fluoro-3-(2-(piperazin-1-yl)ethyl)-1H-indol-4-ol,4-(benzyloxy)-1-ethyl-6-fluoro-3-(2-(isoindolin-2-yl)ethyl)-1H-indole,1-ethyl-6-fluoro-3-(2-(isoindolin-2-yl)ethyl)-1H-indol-4-ol,4-(2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)ethyl)morpholine,(1-(2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)ethyl)pyrrolidin-2-yl)methanol,4-ethoxy-5-fluoro-1-methyl-3-(2-(pyrrolidin-1-yl)ethyl)-1H-indole,5-fluoro-4-methoxy-1-methyl-3-(2-(piperazin-1-yl)ethyl)-1H-indole,3-(2-((1S,4S)-5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)-1-ethyl-6-fluoro-1H-indol-4-ol,5-fluoro-4-methoxy-1-methyl-3-(2-(4-phenylpiperazin-1-yl)ethyl)-1H-indole,3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-5-fluoro-4-methoxy-1-methyl-1H-indole,2-(2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline,8-chloro-3-(2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethyl)-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine,and1-(2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide.

In another aspect, the invention is directed to compounds of formula:

wherein

g is 1, 2 or 3;

R¹ and R² are each independently selected from H, C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted arylalkyl, optionally substituted heteroarylalkyl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocycloalkyl or when taken together with the nitrogen atom to whichthey are attached, R¹ and R² form a 3-8 membered heterocyclic moiety orwhen taken together with the nitrogen atom to which they are attached R¹or R² and A form an optionally substituted 4-8 membered heterocyclyl orheteroaryl moiety;

R³ is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, halogen, orC(O)NR^(d)R^(d′);

W² is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted arylalkyl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, optionallysubstituted heteroarylalkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocycloalkyl, or —C(O)NR^(d)R^(d′);

A is optionally substituted C₁₋₄ alkylene, optionally substitutedcycloalkylene, optionally substituted arylene, optionally substitutedheteroarylene, optionally substituted heterocycloalkylene whereinarylene or heteroarylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, optionally substituted aryl, optionallysubstituted heteroaryl, C₃₋₈ cycloalkyl, —OR^(d), C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂arylalkyl, —S(O)₀₋₂ heteroarylalkyl), —S(O)₀₋₂ cycloalkyl, —S(O)₀₋₂heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d), whereinalkylene and cycloalkylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, oxo, optionally substituted C₁₋₆ alkyl,—S(O)₀₋₂alkyl, —OR^(d) and —NR^(d)R^(d′), aryl or heteroaryl, and C₃-C₈cycloalkyl or 4-8 membered heterocyclyl (e.g., wherein two substituents,together with the carbon to which they are attached, form a ring);

R⁴ is selected from optionally substituted C₁₋₈ alkyl, optionallysubstituted C₁₋₈ heteroalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, —S(O)₂ alkyl,—S(O)₂ heteroalkyl, —S(O)₂ aryl, —S(O)₂ heteroaryl, —S(O)₂ cycloalkyl,—S(O)₂ heterocyclyl, —S(O)₂ heterocycloalkyl, —S(O)₂ arylalkyl, —S(O)₂heteroarylalkyl, —S(O)₂ cycloalkyalkyl, formyl, —OR^(d), —NR^(d)R^(d′),—C(O)OR^(a), —C(O)NR^(d)R^(d′), —S(O)₂NR^(d)R^(d′), C₃₋₈ cycloalkyl,heterocyclyl, cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl,arylalkyl, and heteroarylalkyl, wherein the alkyl, cycloalkyl andheterocyclyl are optionally substituted with 1-3 substituents, halo,alkyl, haloalkyl, heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryland herteroaryl are optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting of halogen,alkyl, heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈haloalkoxy, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂-arylalkyl, —S(O)₀₋₂-heteroarylalkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —OR^(d), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), optionally substituted—C₁alkyl-C(O)NR^(e)R^(f), —C₁alkyl-O-aryl, —C₁alkyl-O-heteroaryl,—C₁alkyl-heterocyclyl, —C₁alkyl-cycloalkyl, cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d);

each R⁶ is independently selected from halo, C₁₋₈ alkyl, aryl,heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ arylalkyl, —S(O)₀₋₂ heteroarylalkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′) cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

R^(a) and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted cycloalkylalkyl and optionallysubstituted heterocycloalkyl;

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety.

In another aspect, the invention is directed to compounds of formula:

wherein

g is 1, 2 or 3;

R¹ and R² are each independently selected from H, C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted arylalkyl, optionally substituted heteroarylalkyl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocycloalkyl or when taken together with the nitrogen atom to whichthey are attached, R¹ and R² form a 3-8 membered heterocyclic moiety orwhen taken together with the nitrogen atom to which they are attached R¹or R² and A form an optionally substituted 4-8 membered heterocyclyl orheteroaryl moiety;

W² is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted arylalkyl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, optionallysubstituted heteroarylalkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocycloalkyl, or —C(O)NR^(d)R^(d′);

A is optionally substituted C₁₋₄ alkylene, optionally substitutedcycloalkylene, optionally substituted arylene, optionally substitutedheteroarylene, wherein arylene or heteroarylene are optionallysubstituted with 1-3 substituents, each of which is independentlyselected from the group consisting of halogen, optionally substitutedaryl, optionally substituted heteroaryl, C₃₋₈ cycloalkyl, —OR^(d), C₁₋₈haloalkoxy, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂ arylalkyl, —S(O)₀₋₂ heteroarylalkyl), —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂—C₁₋₄alkyl-heteroaryl, —NR^(d)S(O)₂—C₁₋₄alkyl-cycloalkyl,—NR^(d)S(O)₂—C₁₋₄alkyl-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted—C₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d),wherein alkylene and cycloalkylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, oxo, optionally substituted C₁₋₆ alkyl,—S(O)₀₋₂alkyl, —OR^(d) and —NR^(d)R^(d′), aryl or heteroaryl, and C₃-C₈cycloalkyl or 4-8 membered heterocyclyl (e.g., wherein two substituents,together with the carbon to which they are attached, form a ring);

R⁴ is selected from optionally substituted C₁₋₈ alkyl, optionallysubstituted C₁₋₈ heteroalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, —S(O)₂ alkyl,—S(O)₂ heteroalkyl, —S(O)₂ aryl, —S(O)₂ heteroaryl, —S(O)₂ cycloalkyl,—S(O)₂ heterocyclyl, —S(O)₂ heterocycloalkyl, —S(O)₂ arylalkyl, —S(O)₂heteroarylalkyl, —S(O)₂ cycloalkyalkyl, formyl, —OR^(d), —NR^(d)R^(d′),—C(O)OR^(a), —C(O)NR^(d)R^(d′), —S(O)₂NR^(d)R^(d′), C₃₋₈ cycloalkyl,heterocyclyl, cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl,arylalkyl, and heteroarylalkyl, wherein the alkyl, cycloalkyl andheterocyclyl are optionally substituted with 1-3 substituents, halo,alkyl, haloalkyl, heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryland heteroaryl are optionally substituted with 1-3 substituents, each ofwhich is independently selected from the group consisting of halogen,alkyl, heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈haloalkoxy, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂-arylalkyl, —S(O)₀₋₂-heteroarylalkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —OR^(d), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), optionally substituted—C₁alkyl-C(O)NR^(e)R^(f), —C₁alkyl-O-aryl, —C₁alkyl-O-heteroaryl,—C₁alkyl-heterocyclyl, —C₁alkyl-cycloalkyl, cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d);

each R⁶ is independently selected from halo, C₁₋₈ alkyl, aryl,heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ arylalkyl, —S(O)₀₋₂ heteroarylalkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′) cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

R^(a) and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted cycloalkylalkyl and optionallysubstituted heterocycloalkyl;

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety.

In another aspect, the invention is directed to compounds of formula:

wherein

g is 1, 2 or 3;

R³ is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, halogen, orC(O)NR^(d)R^(d′);

W² is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted arylalkyl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, optionallysubstituted heteroarylalkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocycloalkyl, or —C(O)NR^(d)R^(d′);

A³ is C₂₋₈-optionally substituted branched alkylene or cycloalkyl,wherein alkylene may form a C₃-C₈ cycloalkyl or 4-8 memberedheterocyclyl;

R⁴ is selected from optionally substituted C₁₋₈ alkyl, optionallysubstituted C₁₋₈ heteroalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, —S(O)₂ alkyl,—S(O)₂ heteroalkyl, —S(O)₂ aryl, —S(O)₂ heteroaryl, —S(O)₂ cycloalkyl,—S(O)₂ heterocyclyl, —S(O)₂ heterocycloalkyl, —S(O)₂ arylalkyl, —S(O)₂heteroarylalkyl, —S(O)₂ cycloalkyalkyl, formyl, —OR^(d), C₁₋₈ aryloxy,C₁₋₈ heteroaryloxy, —NR^(d)R^(d′), C₁₋₈ alkylamino, di(C₁₋₈ alkyl)amino,—C(O)OR^(a), —C(O)NR^(d)R^(d′), —S(O)₂NR^(d)R^(d′), C₃₋₈ cycloalkyl,heterocyclyl, cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl,arylalkyl, and heteroarylalkyl, wherein the alkyl, cycloalkyl andheterocyclyl are optionally substituted with 1-3 substituents, halo,alkyl, haloalkyl, heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryland herteroaryl are optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting of halogen,alkyl, heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈haloalkoxy, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂-arylalkyl, —S(O)₀₋₂-heteroarylalkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), OR^(d), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), optionally substituted—C₁alkyl-C(O)NR^(e)R^(f), —C₁alkyl-O-aryl, —C₁alkyl-O-heteroaryl,—C₁alkyl-heterocyclyl, —C₁alkyl-cycloalkyl, cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d);

each R⁶ is independently selected from halo, C₁₋₈ alkyl, aryl,heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ arylalkyl, —S(O)₀₋₂ heteroarylalkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

R¹³ is selected from hydrogen and methyl; and

R^(a) and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted cycloalkylalkyl and optionallysubstituted heterocycloalkyl;

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety.

In some embodiments, A³ is 1-methylethylene.

In some embodiments, A³ is

In some embodiments, R³ is selected from H, and optionally substitutedC₁₋₈ alkyl.

In some embodiments, R⁴ is selected from optionally substituted C₁₋₈alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —S(O)₂ alkyl,—S(O)₂ arylalkyl, —S(O)₂ heteroarylalkyl, —S(O)₂ aryl, —S(O)₂heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂ heterocycloalkyl, —S(O)₂heterocycloalkylalkyl, and —S(O)₂ cycloalkylalkyl.

In some embodiments, W² is C₁₋₈ alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′), —C(O)NR^(d)R^(d′).

In some embodiments, g is 1.

In some embodiments, each R⁶ is selected from halogen, C₁₋₈ alkyl,hydroxyl, —C₁₋₈ fluoroalkyl, C₁₋₈ haloalkoxy, and —NR^(d)R^(d′).

In some embodiments, the compounds is2-(7-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)propan-1-amine.

In some embodiments, the compound is selected from

wherein R₁₄ is optionally substituted aryl, heteroaryl, alkyl,cycloalkyl, or heterocyclyl. Optionally, R₁₄ and —NHR₁₃ together form a4-8 member heteroalkyl or heteroaryl ring.

In another aspect, the invention is directed to compound of formulae I,II, IV, VII, VIII, IX, XII, XIII, XIV, XV or XVI wherein the compoundcomprises a Positron Emission Tomography (PET) isotope. In someembodiments, the isotope is ¹¹C or ¹⁹F.

In another aspect, the invention is directed to compound of formulae I,II, IV, VII, VIII, IX, XII, XIII, XIV, XV or XVI wherein the compound isenantiomerically enriched for a selected stereoisomer or enantiomer.

In another aspect, the invention is directed to a pharmaceuticalcomposition comprising a compound of formulae I, II, IV, VII, VIII, IX,XII, XIII, XIV, XV or XVI. In some embodiments, the pharmaceuticalcomposition further comprises a Positron Emission Tomography (PET)isotope. In some embodiments, the isotope is ¹¹C or ¹⁹F.

In another aspect, the invention is directed to a method for thetreatment of obesity in a subject, the method comprising administeringto the subject a compound of formulae I, II, IV, VII, VIII, IX, XII,XIII, XIV, XV or XVI, such that obesity is treated in the subject.

In another aspect, the invention is directed to a method for thetreatment of Obsessive Compulsive Disorder (OCD) in a subject, themethod comprising administering to the subject a compound of formulae I,II, IV, VII, VIII, IX, XII, XIII, XIV, XV or XVI, such that OCD istreated in the subject.

In another aspect, the invention is directed to a method for suppressingappetite in a subject, the method comprising administering to thesubject a compound of formulae I, II, IV, VII, VIII, IX, XII, XIII, XIV,XV or XVI, such that appetite is suppressed in the subject.

In another aspect, the invention is directed to a method for thetreatment of schizophrenia or psychosis in a subject, the methodcomprising administering to the subject a compound of formulae I, II,IV, VII, VIII, IX, XII, XIII, XIV, XV or XVI, such that schizophrenia orpsychosis is treated in the subject.

In another aspect, the invention is directed to a method for thetreatment of anxiety or depression in a subject, the method comprisingadministering to the subject a compound of formulae I, II, IV, VII,VIII, IX, XII, XIII, XIV, XV or XVI, such that anxiety or depression istreated in the subject.

In another aspect, the invention is directed to a method for thetreatment of diabetes in a subject, the method comprising administeringto the subject a compound of formulae I, II, IV, VII, VIII, IX, XII,XIII, XIV, XV or XVI, such that diabetes is treated in the subject.

In another aspect, the invention is directed to a method for thetreatment of attention deficit hyperactivity disorder (ADHD) in asubject, the method comprising administering to the subject a compoundof formulae I, II, IV, VII, VIII, IX, XII, XIII, XIV, XV or XVI, suchthat ADHD is treated in the subject.

In another aspect, the invention is directed to a method of modulating(e.g., inhibit or activate) a serotonin receptor (e.g., a 5-HTreceptor), the method comprising contacting a serotonin receptor with acompound of formulae I, II, IV, VII, VIII, IX, XII, XIII, XIV, XV orXVI. In some embodiments, the receptor is a 5-HT_(2A), 5-HT_(2C), and/or5-HT₆ receptor.

In one aspect, the invention is directed to a compound selected from thefollowing formula:

wherein

R^(1a) and R^(2a) are each independently selected from H, optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted aralkyl, optionallysubstituted heteroaralkyl, optionally substituted cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted cycloalkylalkyl,optionally substituted heterocycloalkyl;

R³ is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, halogen, orC(O)NR^(d)R^(d′);

W is

optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocyclyl, optionally substituted cycloalkyl;optionally substituted heteroaralkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocycloalkyl,—C(O)NR^(d)R^(d′), C₁ alkyl substituted with —C(O)NR^(d)R^(d′) or C₂₋₈alkyl substituted with —NR^(d)R^(d′), —C(O)NR^(d)R^(d′) or —OR^(d);

A is optionally substituted C₁₋₄ alkylene, optionally substitutedcycloalkylene, optionally substituted arylene, optionally substitutedheteroarylene, optionally substituted heterocycloalkylene whereinarylene or heteroarylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, C₃₋₈ cycloalkyl, —OR^(d), C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂aralkyl, —S(O)₀₋₂ heteroaralkyl), —S(O)₀₋₂ cycloalkyl, —S(O)₀₋₂heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d),—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d), whereinalkylene and cycloalkylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, oxo, optionally substituted C₁₋₆ alkyl,—S(O)₀₋₂alkyl, —OR^(d) and —NR^(d)R^(d′);

R⁴ is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, —S(O)₂ alkyl, —S(O)₂ heteroalkyl, —S(O)₂ aryl, —S(O)₂heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂ heterocyclyl, —S(O)₂heterocycloalkyl, —S(O)₂ aralkyl, —S(O)₂ heteroaralkyl, —S(O)₂cycloalkyalkyl, formyl, —OR^(d), —NR^(d)R^(d′), —C(O)OR^(a),—C(O)NR^(d)R^(d′), —S(O)₂NR^(d)R^(d′), C₃₋₈ cycloalkyl, heterocyclyl,cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl, aralkyl, andheteroaralkyl, wherein the alkyl, cycloalkyl and heterocyclyl areoptionally substituted with 1-3 substituents, halo, alkyl, haloalkyl,heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryl and herteroarylare optionally substituted with 1-3 substituents, each of which isindependently selected from the group consisting of halogen, alkyl,heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂-aralkyl, —S(O)₀₋₂-heteroaralkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —OR^(d), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d);

R⁵ is selected from H and R⁶;

each R⁶ is independently selected from halo, C₁₋₈ alkyl, aryl,heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, aralkyl,heteroaralkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ aralkyl, —S(O)₀₋₂ heteroaralkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″)NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂—C₁₋₄alkyl-aryl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

each of R⁷ and R⁸ is independently H, optionally substituted C₁₋₈ alkylor fluoro; or R⁷ and R⁸ can, together with the carbon to which they areattached, form a ring;

R^(a), and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl and optionally substitutedheterocycloalkyl;

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety;

g is 1, 2 or 3;

m is 0, 1, 2, 3, 4 or 5; and

n is 2, 3, or 4; and

wherein when m is 0, at least one of R⁷ or R⁸ is not H.

In some embodiments, n is 2.

In some embodiments, R^(1a) and R^(2a) are each independently selectedfrom H, C₁₋₈ alkyl, or optionally substituted aryl.

In some embodiments, R^(1a) and R^(2a) are each independently selectedfrom H or C₁₋₈ alkyl.

In some embodiments, R^(1a) and R^(2a) are H.

In some embodiments, R^(1a) and R^(2a) are each optionally substitutedC₁₋₈ alkyl (e.g., methyl).

In some embodiments, R^(1a) is H and R^(2a) is optionally substitutedC₁₋₈ alkyl (e.g., methyl)

In some embodiments, R^(1a) is optionally substituted C₁₋₈ alkyl andR^(2a) is H.

In some embodiments, A is selected from optionally substituted C₁₋₄alkylene, wherein the C₁₋₄ alkylene is optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen (e.g., fluorine), hydroxyl, optionally substitutedC₁₋₆ alkyl, C₁₋₈ alkoxy, —SO₂ alkyl, and —NR^(d)R^(d′).

In some embodiments, A is selected from optionally substituted C₁₋₄alkylene, wherein the C₁₋₄ alkylene is optionally substituted with —SO₂alkyl (e.g., methylsulfone).

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with hydroxyl

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting of halogen(e.g., fluorine).

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl (e.g., methyl, ethyl, i-propyl, —C₁₋₂alkyl-OH, —C₁₋₂ alkyl-CF₃, —C₁₋₂ alkyl-CHF₂, —C₁₋₂ alkyl-CH₂F, —C₁₋₂alkyl-NR^(d)R^(d′)).

In some embodiments, A is optionally substituted C₁₋₄ alkylene (e.g.,methylene, ethylene, propylene or butylene).

In some embodiments, A is optionally substituted ethylene

In some embodiments, R³ is selected from H, and optionally substitutedC₁₋₈ alkyl.

In some embodiments, R³ is C₁₋₈ alkyl (e.g., —C₁₋₄ alkyl-OR^(d), —C₁₋₄alkyl-NR^(d)R^(d′), or —C₁₋₄ alkyl-C(O)NR^(d)R^(d′)).

In some embodiments, R³ is H.

In some embodiments, R³ is halogen (e.g., fluorine).

In some embodiments, R³ is optionally substituted aryl.

In some embodiments, R³ is optionally substituted heteroaryl.

In some embodiments, R⁴ is selected from C₁₋₈ alkyl, aryl, heteroaryl,aralkyl, heteroaralkyl, —S(O)₂ alkyl, —S(O)₂ aralkyl, —S(O)₂heteroaralkyl, —S(O)₂ aryl, —S(O)₂ heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂heterocycloalkyl, —S(O)₂ heterocycloalkylalkyl, and —S(O)₂cycloalkylalkyl.

In some embodiments, R⁴ is C₁₋₈ alkyl (e.g., methyl or ethyl).

In some embodiments, R⁴ is C₁₋₈ alkyl, optionally substituted with 1-3fluorine substituents (e.g., —CF₃, —C₁ alkyl-CF₃, —C₁ alkyl-CHF₂, —C₁alkyl-CH₂F).

In some embodiments, W is C₂₋₈ alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′), or —C(O)NR^(d)R^(d′).

In some embodiments, W is

or optionally substituted aryl.

In some embodiments, W is

In some embodiments, W is

wherein m is 1-3 and R⁵ is selected from F, Cl, Br, CF₃, methyl, OH,OCF₃, or S(O)₀₋₂R^(a).

In some embodiments, W is

wherein m is 1-3, R⁷ and R⁸ are H and R⁵ is selected from F, Cl, Br,CF₃, methyl, OH, —OCH₃, —OCF₃, S(O)₀₋₂R^(a).

In some embodiments, W is optionally substituted heteroaryl (e.g.,pyridine, thiophene, furan, isoxazole, oxazole, pyrimidine, pyrazine orthiazole).

In some embodiments, W is optionally substituted heteroaralkyl (e.g., C₁alkyl-heteroaryl).

In some embodiments, W is optionally substituted aryl (e.g., monocyclicaryl).

In some embodiments, W is optionally substituted monocyclic aryl (e.g.,phenyl).

In some embodiments, W is optionally substituted phenyl (e.g., aniline,halophenyl, alkoxyphenyl, alkylphenyl, benzoic acid, benzamide ornitrophenyl).

In some embodiments, W is

In some embodiments, m is 0.

In some embodiments, m is 1.

In some embodiments, m is 2.

In some embodiments, each R⁵ is selected from C₁₋₈ alkyl, C₁₋₈fluoroalkyl, hydroxyl, C₁₋₈ alkoxy, C₁₋₈ fluoroalkoxy, nitro, halogen,and —NR^(d)R^(d′).

In some embodiments, each R⁵ is selected from H, C₁₋₈ alkyl, C₁₋₈alkoxy, C₁₋₈ fluoroalkyl, halogen, hydroxyl, C₁₋₈ fluoroalkoxy, nitroand amino.

In some embodiments, each R⁵ is selected from H, C₁₋₈ alkyl, C₁₋₈fluoroalkyl, C₁₋₈ fluoroalkoxy, amino, nitro and halogen.

In some embodiments, each R⁵ is C₁₋₈ alkyl (e.g., methyl).

In some embodiments, each R⁵ is C₁₋₈ fluoroalkyl (e.g.,trifluoromethyl).

In some embodiments, each R⁵ is C₁₋₈ fluoroalkoxy (e.g.,trifluoromethoxy).

In some embodiments, each R⁵ is halogen (e.g., chlorine or fluorine).

In some embodiments, each R⁵ is H.

In some embodiments, g is 1.

In some embodiments, g is 2.

In some embodiments, each R⁶ is selected from halogen, C₁₋₈ alkyl,hydroxyl, —C₁₋₈ fluoroalkyl, C₁₋₈ haloalkoxy, and —NR^(d)R^(d′).

In some embodiments, each R⁶ is selected from halogen, hydroxyl, —C₁₋₈fluoroalkyl, —C₁₋₈ fluoroalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′), aryl, heteroaryl, and C₁₋₈ alkyl.

In some embodiments, each R⁶ is halogen (e.g., fluorine or chlorine).

In some embodiments, each R⁶ is C₁₋₈ alkyl (e.g., methyl).

In some embodiments, each R⁶ is C₁₋₈ fluoroalkyl (e.g., CF₃).

In some embodiments, each R⁶ is C₁₋₈ fluoroalkoxy (e.g., —OCF₃).

In some embodiments, each R⁶ is aryl (e.g., phenyl).

In some embodiments, each R⁶ is heteroaryl (e.g., pyridine).

In some embodiments, each R⁶ is heterocyclyl further substituted witharyl.

In some embodiments, each R⁶ is heterocyclyl further substituted withheteroaryl.

In some embodiments, a compound of Formula I is enantiomericallyenriched (e.g., having an ee >60%, >70%, >80%, >90%, >95%, >97%, >98% or>99%).

In some embodiments, the compound is selected from the followingformulas:

In some embodiments, the compound is selected from the followingformulas:

In some embodiments, the compound is selected from the followingformulas:

In another aspect, the invention is directed to a compound selected fromthe following formula:

wherein

g is 1, 2 or 3;

A¹ is optionally substituted C₃₋₆cycloalkylene, optionally substitutedheterocyclylene, optionally substituted arylene, optionally substitutedheteroarylene, optionally substituted heterocycloalkylene or optionallysubstituted —C(O)—C₁₋₃ alkylene-, wherein arylene or heteroarylene areoptionally substituted with 1-3 substituents, each of which isindependently selected from the group consisting of halogen, C₃₋₈cycloalkyl, —OR^(d), C₁₋₈ haloalkoxy, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂ aralkyl, —S(O)₀₋₂ heteroaralkyl,—S(O)₀₋₂ C₁₋₈ cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂heterocycloalkylalkyl, —S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′) optionally substituted —C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d), whereincycloalkylene and —C(O)—C₁₋₃ alkylene are optionally substituted with1-3 substituents, each of which is independently selected from the groupconsisting of halogen, oxo, optionally substituted C₁₋₆ alkyl, C₁₋₈alkoxy, —S(O)₀₋₂alkyl, —OR^(d) and —NR^(d)R^(d′);

R¹ and R² are each independently selected from H, C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aralkyl, optionally substituted heteroaralkyl, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocycloalkyl orwhen taken together with the nitrogen atom to which they are attached,R¹ and R² form a 3-8 membered heterocyclic moiety or when taken togetherwith the nitrogen atom to which they are attached R¹ or R² and A form anoptionally substituted 4-8 membered heterocyclyl or heteroaryl moiety;

R³ is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, halogen, orC(O)NR^(d)R^(d′);

W¹ is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aralkyl, optionally substituted cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted cycloalkylalkyl,optionally substituted heterocycloalkyl or optionally substitutedheteroaralkyl;

R⁴ is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, —S(O)₂ alkyl, —S(O)₂ heteroalkyl, —S(O)₂ aryl, —S(O)₂heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂ heterocyclyl, —S(O)₂heterocycloalkyl, —S(O)₂ aralkyl, —S(O)₂ heteroaralkyl, —S(O)₂cycloalkyalkyl, formyl, —OR^(d), —NR^(d)R^(d′), —C(O)OR^(a),—C(O)NR^(d)R^(d′), —S(O)₂NR^(d)R^(d′), C₃₋₈ cycloalkyl, heterocyclyl,cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl, aralkyl, andheteroaralkyl, wherein the alkyl, cycloalkyl and heterocyclyl areoptionally substituted with 1-3 substituents, halo, alkyl, haloalkyl,heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryl and heteroaryl areoptionally substituted with 1-3 substituents, each of which isindependently selected from the group consisting of halogen, alkyl,heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂-aralkylaryl, —S(O)₀₋₂-heteroaralkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —OR^(d), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d);

each R⁶ is independently selected from halo, C₁₋₈ alkyl, aryl,heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, aralkyl,heteroaralkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ aralkyl, —S(O)₀₋₂ heteroaralkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

R^(a), and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl and optionally substitutedheterocycloalkyl; and

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety.

In some embodiments, R³ is selected from H, and optionally substitutedC₁₋₈ alkyl.

In some embodiments, R³ is optionally substituted C₁₋₈ alkyl (e.g.,—C₁₋₄ alkyl-OR^(d), —C₁₋₄ alkyl-NR^(d)R^(d′), or —C₁₋₄alkyl-C(O)NR^(d)R^(d′)).

In some embodiments, A¹ is optionally substituted aryl.

In some embodiments, A¹ is optionally substituted heteroaryl.

In some embodiments, A¹ is aryl (e.g. phenyl).

In some embodiments, W¹ is hydrogen, optionally substituted C₁₋₈ alkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted aralkyl, or optionally substituted heteroaralkyl

In some embodiments, W¹ is H, optionally substituted C₁₋₈ alkyl.,arylalkyl, or heteroaralkyl.

In some embodiments, W¹ is optionally substituted C₁₋₈ alkyl (e.g.,—CF₃, —CH₂CF₃, or —CF₂CF₃)

In some embodiments, W¹ is C₁₋₈ alkyl. (e.g., methyl or ethyl).

In some embodiments, W¹ is arylalkyl (e.g. benzyl).

In some embodiments, a compound of Formula II is enantiomericallyenriched (e.g., having an ee >60%, >70%, >80%, >90%, >95%, >97%, >98% or>99%).

In another aspect, the invention is directed to a compound selected fromthe following formula:

wherein

g′ is 0, 1, 2 or 3;

Z is an optionally substituted heteroaryl or optionally substitutedheterocyclyl;

R¹ and R² are each independently selected from H, C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aralkyl, optionally substituted heteroaralkyl, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocycloalkyl orwhen taken together with the nitrogen atom to which they are attached,R¹ and R² form a 3-8 membered heterocyclic moiety or when taken togetherwith the nitrogen atom to which they are attached R¹ or R² and A form anoptionally substituted 4-8 membered heterocyclyl or heteroaryl moiety;

R³ is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, halogen, orC(O)NR^(d)R^(d′);

A is optionally substituted C₁₋₄ alkylene, optionally substitutedcycloalkylene, optionally substituted arylene, optionally substitutedheteroarylene, optionally substituted heterocycloalkylene whereinarylene or heteroarylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, C₃₋₈ cycloalkyl, —OR^(d), C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂aralkyl, —S(O)₀₋₂ heteroaralkyl), —S(O)₀₋₂ cycloalkyl, —S(O)₀₋₂heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted —C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d), whereinalkylene and cycloalkylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, oxo, optionally substituted C₁₋₆ alkyl,—S(O)₀₋₂alkyl, —OR^(d) and —NR^(d)R^(d′);

R⁴ is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, —S(O)₂ alkyl, —S(O)₂ heteroalkyl, —S(O)₂ aryl, —S(O)₂heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂ heterocyclyl, —S(O)₂heterocycloalkyl, —S(O)₂ aralkyl, —S(O)₂ heteroaralkyl, —S(O)₂cycloalkyalkyl, formyl, —OR^(d), —NR^(d)R^(d′), —C(O)OR^(a),—C(O)NR^(d)R^(d′), —S(O)₂NR^(d)R^(d′), C₃₋₈ cycloalkyl, heterocyclyl,cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl, aralkyl, andheteroaralkyl, wherein the alkyl, cycloalkyl and heterocyclyl areoptionally substituted with 1-3 substituents, halo, alkyl, haloalkyl,heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryl and herteroarylare optionally substituted with 1-3 substituents, each of which isindependently selected from the group consisting of halogen, alkyl,heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂—C₁₋₄alkylaryl, —S(O)₀₋₂—C₁₋₄alkylheteroaryl,—OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b),—OR^(d), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl,—NR^(d)S(O)₂cycloalkyl, —NR^(d)S(O)₂heterocycloalkyl,—NR^(d)S(O)₂-aralkyl, —NR^(d)S(O)₂-heteroaralkyl,—NR^(d)S(O)₂-cycloalkylalkyl, —NR^(d)S(O)₂-heterocycloalkyl,—SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,—NR^(d)R^(d′), optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a),—C(O)NR^(d)R^(d′), and —C(O)OR^(d);

each R⁶ is independently selected from halo, C₁₋₈ alkyl, aryl,heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, aralkyl,heteroaralkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ aralkyl, —S(O)₀₋₂ heteroaralkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

R^(a), and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl and optionally substitutedheterocycloalkyl, or when taken together with the nitrogen atom to whichthey are attached, R^(a) and R^(b) form a 4-8 membered heterocyclicmoiety; and

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety.

In some embodiments, R¹ and R² are each independently selected from H,C₁₋₈ alkyl, and optionally substituted aryl.

In some embodiments, R¹ and R² are each independently selected from Hand C₁₋₈ alkyl.

In some embodiments, R¹ and R² are H.

In some embodiments, R¹ and R² are each optionally substituted C₁₋₈alkyl (e.g., methyl).

In some embodiments, R¹ is H and R² is optionally substituted C₁₋₈ alkyl(e.g., methyl)

In some embodiments, R¹ is optionally substituted C₁₋₈ alkyl and R² isH.

In some embodiments, A is selected from optionally substituted C₁₋₄alkylene, wherein the C₁₋₄ alkylene is optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen (e.g., fluorine), hydroxyl, optionally substitutedC₁₋₆ alkyl, C₁₋₈ alkoxy, —SO₂ alkyl, and —NR^(d)R^(d′).

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with —SO₂ alkyl (e.g.,methylsulfone).

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with hydroxyl

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting of halogen(e.g., fluorine).

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl (e.g., methyl, ethyl, i-propyl, —C₁₋₂alkyl-OH, —C₁₋₂ alkyl-CF₃, —C₁₋₂ alkyl-CHF₂, —C₁₋₂ alkyl-CH₂F, —C₁₋₂alkyl-NR^(d)R^(d′)).

In some embodiments, A is optionally substituted C₁₋₄ alkylene (e.g.,methylene, ethylene, propylene or butylene).

In some embodiments, A is optionally substituted ethylene

In some embodiments, R³ is selected from H, and optionally substitutedC₁₋₈ alkyl.

In some embodiments, R³ is C₁₋₈ alkyl (e.g., —C₁₋₄ alkyl-OR^(d), —C₁₋₄alkyl-NR^(d)R^(d′), or —C₁₋₄ alkyl-C(O)NR^(d)R^(d′)).

In some embodiments, R³ is H.

In some embodiments, R³ is halogen (e.g., fluorine).

In some embodiments, R³ is optionally substituted aryl.

In some embodiments, R³ is optionally substituted heteroaryl.

In some embodiments, R⁴ is selected from C₁₋₈ alkyl, aryl, heteroaryl,aralkyl, heteroaralkyl, —S(O)₂ alkyl, —S(O)₂ aralkyl, —S(O)₂heteroaralkyl, —S(O)₂ aryl, —S(O)₂ cycloalkyl, —S(O)₂ heterocycloalkyl,—S(O)₂ heterocycloalkylalkyl, —S(O)₂ cycloalkylalkyl, and —S(O)₂heteroaryl.

In some embodiments, R⁴ is selected from C₁₋₈ alkyl (e.g., methyl orethyl).

In some embodiments, R⁴ is C₁₋₈ alkyl, optionally substituted with 1-3fluorine substituents (e.g., —C₁ alkyl-CF₃, —CF₃, —C₁-alkyl-CHF₂, or—C₁alkyl-CH₂F).

In some embodiments,

is optionally substituted heteroaryl.

In some embodiments,

is 5-14 membered heteroaryl.

In some embodiments,

is optionally substituted heterocycyl.

In some embodiments,

is 5-14 membered heterocyclyl.

In some embodiments,

is optionally substituted

In some embodiments,

is optionally substituted on a carbon and/or nitrogen.

The compound according to claim xx, wherein

In some embodiments, a compound of Formula IV is enantiomericallyenriched (e.g., having an ee >60%, >70%, >80%, >90%, >95%, >97%, >98% or>99%).

In another aspect, the invention is directed to a compound selected fromthe following formula:

wherein

R¹ and R² are each independently selected from H, C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aralkyl, optionally substituted heteroaralkyl, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocycloalkyl orwhen taken together with the nitrogen atom to which they are attached,R¹ and R² form a 3-8 membered heterocyclic moiety or when taken togetherwith the nitrogen atom to which they are attached R¹ or R² and A form anoptionally substituted 4-8 membered heterocyclyl or heteroaryl moiety;

R³ is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, halogen, orC(O)NR^(d)R^(d′);

W² is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocycloalkyl, or—C(O)NR^(d)R^(d′);

A is optionally substituted C₁₋₄ alkylene, optionally substitutedcycloalkylene, optionally substituted arylene, optionally substitutedheteroarylene, optionally substituted heterocycloalkylene whereinarylene or heteroarylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, C₃₋₈ cycloalkyl, —OR^(d), C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂aralkyl, —S(O)₀₋₂ heteroaralkyl), —S(O)₀₋₂ cycloalkyl, —S(O)₀₋₂heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d), whereinalkylene and cycloalkylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, oxo, optionally substituted C₁₋₆ alkyl,—S(O)₀₋₂alkyl, —OR^(d) and —NR^(d)R^(d′);

R⁴ is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, —S(O)₂ alkyl, —S(O)₂ heteroalkyl, —S(O)₂ aryl, —S(O)₂heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂ heterocyclyl, —S(O)₂heterocycloalkyl, —S(O)₂ aralkyl, —S(O)₂ heteroaralkyl, —S(O)₂cycloalkyalkyl, formyl, —OR^(d), —NR^(d)R^(d′), —C(O)OR^(a),—C(O)NR^(d)R^(d′), —S(O)₂NR^(d)R^(d′), C₃₋₈ cycloalkyl, heterocyclyl,cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl, aralkyl, andheteroaralkyl, wherein the alkyl, cycloalkyl and heterocyclyl areoptionally substituted with 1-3 substituents, halo, alkyl, haloalkyl,heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryl and herteroarylare optionally substituted with 1-3 substituents, each of which isindependently selected from the group consisting of halogen, alkyl,heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂-aralkyl, —S(O)₀₋₂-heteroaralkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —OR^(d), NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d);

each R^(6′) is independently selected from hydrogen, halo, C₁₋₈ alkyl,aryl, heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, aralkyl,heteroaralkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ aralkyl, —S(O)₀₋₂ heteroaralkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′),and —C(O)OR^(d), wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

R^(6″) is optionally substituted aryl, heteroaryl, heterocyclyl,cycloalkyl, —OR^(d), C₂₋₈ alkynyl, —NH-aryl, —NH-heteroaryl, —NH-alkyl,—NR^(d)-aryl, —NR^(d)-heteroaryl, —NR^(d)-arylalkyl,—NR^(d)-heteroarylalkyl, —NR^(d)-heterocyclyl,—NR^(d)-heterocyclylalkyl, —NR^(d)-heterocyclyl, —NR^(d)-cyclylalkyl,—NR^(d)-alkyl, —C₁alkyl-aryl, —C₁alkyl-heteroaryl, heterocyclyl,—C₁alkyl-cycloalkyl, —C₁alkyl-NR^(d)-alkyl, aryloxy, and heteroaryloxy;and

R^(a), and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl and optionally substitutedheterocycloalkyl;

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety.

In some embodiments, the compound is selected from:

-   2-(7-fluoro-4-methoxy-1-methyl-5-phenyl-1H-indol-3-yl)-N,N-dimethylethanamine,-   2-(4-methoxy-1-methyl-7-(pyridin-3-yl)-1H-indol-3-yl)-N,N-dimethylethanamine,-   2-(4-methoxy-1-methyl-7-phenyl-1H-indol-3-yl)-N,N-dimethylethanamine,-   2-(4-methoxy-1-methyl-7-(thiophen-3-yl)-1H-indol-3-yl)-N,N-dimethylethanamine,-   2-(4-methoxy-1-methyl-7-(thiophen-2-yl)-1H-indol-3-yl)-N,N-dimethylethanamine,-   2-(7-(furan-2-yl)-4-methoxy-1-methyl-1H-indol-3-yl)-N,N-dimethylethanamine,-   2-(7-(furan-3-yl)-4-methoxy-1-methyl-1H-indol-3-yl)-N,N-dimethylethanamine,-   2-(4-methoxy-1-methyl-7-(1H-pyrrol-2-yl)-1H-indol-3-yl)-N,N-dimethylethanamine,-   3-(3-(2-(dimethylamino)ethyl)-4-methoxy-1-methyl-1H-indol-7-yl)prop-2-yn-1-ol,    and-   3-(2-(dimethylamino)ethyl)-4-methoxy-1-methyl-N-phenyl-1H-indol-7-amine.

In some embodiments, R¹ and R² are each independently selected from H,C₁₋₈ alkyl, and optionally substituted aryl.

In some embodiments, R¹ and R² are each independently selected from Hand C₁₋₈ alkyl.

In some embodiments, R¹ and R² are H.

In some embodiments, R¹ and R² are each optionally substituted C₁₋₈alkyl (e.g., methyl).

In some embodiments, R¹ is H and R² is optionally substituted C₁₋₈ alkyl(e.g., methyl)

In some embodiments, R¹ is optionally substituted C₁₋₈ alkyl and R² isH.

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting of halogen(e.g., fluorine), hydroxyl, optionally substituted C₁₋₆ alkyl, C₁₋₈alkoxy, —SO₂ alkyl, and —NR^(d)R^(d′).

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with —SO₂ alkyl (e.g.,methylsulfone).

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with hydroxyl

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting of halogen(e.g., fluorine).

In some embodiments, A optionally substituted C₁₋₄ alkylene, wherein theC₁₋₄ alkylene is optionally substituted with 1-3 substituents, each ofwhich is independently selected from the group consisting of optionallysubstituted C₁₋₆ alkyl (e.g., methyl, ethyl, i-propyl, —C₁₋₂ alkyl-OH,—C₁₋₂ alkyl-CF₃, —C₁₋₂ alkyl-CHF₂, —C₁₋₂ alkyl-CH₂F, —C₁₋₂alkyl-NR^(d)R^(d′)).

In some embodiments, A is optionally substituted C₁₋₄ alkylene (e.g.,methylene, ethylene, propylene or butylene).

In some embodiments, A is optionally substituted ethylene

In some embodiments, R³ is selected from H, and optionally substitutedC₁₋₈ alkyl.

In some embodiments, R³ is C₁₋₈ alkyl (e.g., —C₁₋₄ alkyl-OR^(d), —C₁₋₄alkyl-NR^(d)R^(d′), or —C₁₋₄ alkyl-C(O)NR^(d)R^(d′)).

In some embodiments, R³ is H.

In some embodiments, R³ is halogen (e.g., fluorine).

In some embodiments, R³ is optionally substituted aryl.

In some embodiments, R³ is optionally substituted heteroaryl.

In some embodiments, R⁴ is selected from C₁₋₈ alkyl, aryl, heteroaryl,aralkyl, heteroaralkyl, —S(O)₂ alkyl, —S(O)₂ aralkyl, —S(O)₂heteroaralkyl, —S(O)₂ aryl, —S(O)₂ cycloalkyl, —S(O)₂ heterocycloalkyl,—S(O)₂ heterocycloalkylalkyl, —S(O)₂ cycloalkylalkyl, and —S(O)₂heteroaryl.

In some embodiments, R⁴ is selected from C₁₋₈ alkyl (e.g., methyl orethyl).

In some embodiments, R⁴ is selected from C₁₋₈ alkyl, optionallysubstituted with 1-3 fluorine substituents (e.g., —C₁alkyl-CF₃, —CF₃,—C₁-alkyl-CHF₂, and —C₁-alkyl-CH₂F).

In some embodiments, W² is C₁₋₈ alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′), —C(O)NR^(d)R^(d′).

In some embodiments, W² is C₂₋₈ alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′), —C(O)NR^(d)R^(d′).

In some embodiments, W² is H.

In some embodiments, W² is optionally substituted C₁₋₈ alkyl.

In some embodiments, W² is optionally substituted C₁₋₈ alkyl (e.g.,—CF₃, —CF₂CF₃, or —CH₂CF₃).

In some embodiments, W² is C₁₋₈ alkyl (e.g. methyl or ethyl).

In some embodiments, W² is optionally substituted aralkyl (e.g.,benzyl). In some embodiments, R^(6′) is selected from hydrogen, halogen,C₁₋₈ alkyl, C₁₋₈ fluoroalkyl, C₁₋₈ haloalkoxy, cycloalkyl, and C₁₋₈fluoroalkoxy.

In some embodiments, R^(6′) is C₁₋₈ fluoroalkoxy (e.g., —OCF₃).

In some embodiments, R^(6′) is selected from hydrogen, halogen and C₁₋₈alkyl.

In some embodiments, R^(6′) is selected from hydrogen and halogen.

In some embodiments, R^(6′) is hydrogen.

In some embodiments, R^(6′) is halogen (e.g., fluorine).

In some embodiments, R^(6″) is selected from optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted aryloxy,optionally substituted heteroaryloxy, —NH-aryl and C₁₋₈ alkynoxy.

In some embodiments, R^(6″) is selected from optionally substitutedaryl, optionally substituted heteroaryl, —NH-aryl, hydroxyl, and C₂₋₈alkynyl.

In some embodiments, R^(6″) is optionally substituted aryl (e.g.,monocyclic aryl) In some embodiments, R^(6″) is optionally substitutedmonocyclic aryl (e.g., phenyl).

In some embodiments, R^(6″) is optionally substituted heteroaryl (e.g.,monocyclic heteroaryl).

In some embodiments, R^(6″) is optionally substituted monocyclicheteroaryl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-thionyl, 2-thionyl,2-furanyl, 3-furanyl or 2-pyrollyl).

In some embodiments, R^(6″) is —NH-aryl (e.g., NHphenyl).

In some embodiments, R^(6′) is hydroxyl C₂₋₈ alkynyl

In some embodiments, a compound of Formula VII is enantiomericallyenriched (e.g., having an ee >60%, >70%, >80%, >90%, >95%, >97%, >98% or>99%).

In another aspect, the invention is directed to a compound selected fromthe following formula:

wherein

g is 1, 2 or 3;

R^(1a) is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aralkyl, optionally substituted heteroaralkyl, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocycloalkyl;

Q is selected from is aryl, heteroaryl, aralkyl, heterocycloalkyl orheteroaralkyl, wherein Q is optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, C₃₋₈ cycloalkyl, —OR^(d), C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂aralkyl, —S(O)₀₋₂ heteroaralkyl), —S(O)₀₋₂ cycloalkyl, —S(O)₀₋₂heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted —C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O);

R³ is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, halogen, orC(O)NR^(d)R^(d′);

W² is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocycloalkyl, or—C(O)NR^(d)R^(d′);

A is optionally substituted C₁₋₄ alkylene, optionally substitutedcycloalkylene, optionally substituted arylene, optionally substitutedheteroarylene, wherein arylene or heteroarylene are optionallysubstituted with 1-3 substituents, each of which is independentlyselected from the group consisting of halogen, C₃₋₈ cycloalkyl, —OR^(d),C₁₋₈ haloalkoxy, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ aralkyl, —S(O)₀₋₂ heteroaralkyl),—OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(a),—NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl,—NR^(d)S(O)₂cycloalkyl, —NR^(d)S(O)₂heterocycloalkyl,—NR^(d)S(O)₂-aralkyl, —NR^(d)S(O)₂—C₁₋₄alkyl-heteroaryl,—NR^(d)S(O)₂—C₁₋₄alkyl-cycloalkyl,—NR^(d)S(O)₂—C₁₋₄alkyl-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substitutedC₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d),wherein alkylene and cycloalkylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of fluorine, oxo, optionally substituted C₁₋₆ alkyl,—S(O)₀₋₂alkyl, —OR^(d) and —NR^(d)R^(d′);

R⁴ is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, —S(O)₂ alkyl, —S(O)₂ heteroalkyl, —S(O)₂ aryl, —S(O)₂heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂ heterocyclyl, —S(O)₂heterocycloalkyl, —S(O)₂ aralkyl, —S(O)₂ heteroaralkyl, —S(O)₂cycloalkyalkyl, formyl, —OR^(d), —NR^(d)R^(d′), —C(O)OR^(a),—C(O)NR^(d)R^(d′), —S(O)₂NR^(d)R^(d′), C₃₋₈ cycloalkyl, heterocyclyl,cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl, aralkyl, andheteroaralkyl, wherein the alkyl, cycloalkyl and heterocyclyl areoptionally substituted with 1-3 substituents, halo, alkyl, haloalkyl,heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryl and herteroarylare optionally substituted with 1-3 substituents, each of which isindependently selected from the group consisting of halogen, alkyl,heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂-aralkyl, —S(O)₀₋₂-heteroaralkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —OR^(d), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d);

each R⁶ is independently selected from halo, C₁₋₈ alkyl, aryl,heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, aralkyl,heteroaralkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ aralkyl, —S(O)₀₋₂ heteroaralkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″)NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

R^(a), and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl and optionally substitutedheterocycloalkyl;

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety.

In some embodiments, the compound isN-(2-(1-ethyl-7-fluoro-4-methoxy-1H-indol-3-yl)ethyl)aniline.

In some embodiments, R^(1a) is selected from H, C₁₋₈ alkyl, andoptionally substituted aryl.

In some embodiments, R^(1a) is selected from H and C₁₋₈ alkyl.

In some embodiments, R^(1a) is H.

In some embodiments, R^(1a) is optionally substituted C₁₋₈ alkyl (e.g.,methyl).

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting of halogen(e.g., fluorine), hydroxyl, optionally substituted C₁₋₆ alkyl, C₁₋₈alkoxy, —SO₂ alkyl, and —NR^(d)R^(d′).

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with —SO₂ alkyl (e.g.,methylsulfone).

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with hydroxyl

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting of halogen(e.g., fluorine).

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl (e.g., methyl, ethyl, i-propyl, —C₁₋₂alkyl-OH, —C₁₋₂ alkyl-CF₃, —C₁₋₂ alkyl-CHF₂, —C₁₋₂ alkyl-CH₂F, —C₁₋₂alkyl-NR^(d)R^(d′)).

In some embodiments, A is optionally substituted C₁₋₄ alkylene (e.g.,methylene, ethylene, propylene or butylene).

In some embodiments, A is optionally substituted ethylene

In some embodiments, R³ is selected from H, and optionally substitutedC₁₋₈ alkyl.

In some embodiments, R³ is C₁₋₈ alkyl (e.g., —C₁₋₄ alkyl-OR^(d), —C₁₋₄alkyl-NR^(d)R^(d′), or —C₁₋₄ alkyl-C(O)NR^(d)R^(d′)).

In some embodiments, R³ is H.

In some embodiments, R³ is halogen (e.g., fluorine).

In some embodiments, R³ is optionally substituted aryl.

In some embodiments, R³ is optionally substituted heteroaryl.

In some embodiments, R⁴ is selected from C₁₋₈ alkyl, aryl, heteroaryl,aralkyl, heteroaralkyl, —S(O)₂ alkyl, —S(O)₂ aralkyl, —S(O)₂heteroaralkyl, —S(O)₂ aryl, —S(O)₂ cycloalkyl, —S(O)₂ heterocycloalkyl,—S(O)₂ heterocycloalkylalkyl, —S(O)₂ cycloalkylalkyl and —S(O)₂heteroaryl.

In some embodiments, R⁴ is selected from C₁₋₈ alkyl (e.g., methyl orethyl).

In some embodiments, R⁴ is selected from C₁₋₈ alkyl, optionallysubstituted with 1-3 fluorine substituents (e.g., —C₁-alkyl-CF₃,—C₁-alkyl-CH₂F, —C₁-alkyl-CHF₂, —CF₃).

In some embodiments, W² is C₁₋₈ alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′), —C(O)NR^(d)R^(d′).

In some embodiments, W² is C₂₋₈ alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′), —C(O)NR^(d)R^(d′).

In some embodiments, W² is H.

In some embodiments, W² is optionally substituted C₁₋₈ alkyl.

In some embodiments, W² is optionally substituted C₁₋₈ alkyl (e.g.,—CF₃, —CF₂CF₃, or —CH₂CF₃).

In some embodiments, W² is C₁₋₈ alkyl (e.g. methyl or ethyl).

In some embodiments, W² is optionally substituted aralkyl (e.g.,benzyl). In some embodiments, W² is C₁₋₈ alkyl (e.g., methyl).

In some embodiments, Q is optionally substituted aryl or optionallysubstituted heteroaryl.

In some embodiments, Q is optionally substituted aryl (e.g., monocyclicaryl).

In some embodiments, Q is optionally substituted monocyclic aryl (e.g.,phenyl).

In some embodiments, Q is optionally substituted arylalkyl.

In some embodiments, Q is optionally substituted heteroarylalkyl.

In some embodiments, Q is arylalkyl (e.g. benzyl).

In some embodiments, each R⁶ is selected from halogen, C₁₋₈ alkyl,hydroxyl, —C₁₋₈ fluoroalkyl, amino, and —NR^(d)R^(d′).

In some embodiments, each R⁶ is selected from halogen, hydroxyl, —C₁₋₈fluoroalkyl, —C₁₋₈ fluoroalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′), aryl, heteroaryl, and C₁₋₈ alkyl.

In some embodiments, each R⁶ is halogen (e.g., fluorine or chlorine).

In some embodiments, each R⁶ is C₁₋₈ alkyl (e.g., methyl).

In some embodiments, each R⁶ is C₁₋₈ fluoroalkyl (e.g., CF₃).

In some embodiments, each R⁶ is C₁₋₈ fluoroalkoxy (e.g., —OCF₃).

In some embodiments, each R⁶ is aryl (e.g., phenyl).

In some embodiments, each R⁶ is heteroaryl (e.g., pyridine).

In some embodiments, each R⁶ is heterocyclyl further substituted witharyl.

In some embodiments, each R⁶ is heterocyclyl further substituted withheteroaryl.

In some embodiments, a compound of Formula VIII is enantiomericallyenriched (e.g., having an ee >60%, >70%, >80%, >90%, >95%, >97%, >98% or>99%).

In another aspect, the invention is directed to a compound selected fromformula:

L is a bond, —SO₂—, or optionally substituted C₁₋₃ alkylene;

M is optionally substituted C₁₋₈ alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted aralkyl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocycloalkyl or optionally substituted heteroaralkyl;

R¹ and R² are each independently selected from H, C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aralkyl, optionally substituted heteroaralkyl, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocycloalkyl orwhen taken together with the nitrogen atom to which they are attached,R¹ and R² form a 3-8 membered heterocyclic moiety or when taken togetherwith the nitrogen atom to which they are attached R¹ or R² and A form anoptionally substituted 4-8 membered heterocyclyl or heteroaryl moiety;

R³ is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, halogen, orC(O)NR^(d)R^(d′);

W² is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocycloalkyl, or—C(O)NR^(d)R^(d′);

A is optionally substituted C₁₋₄ alkylene, optionally substitutedcycloalkylene, optionally substituted arylene, optionally substitutedheteroarylene, optionally substituted heterocycloalkylene whereinarylene or heteroarylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, C₃₋₈ cycloalkyl, —OR^(d), C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂aralkyl, —S(O)₀₋₂ heteroaralkyl), —S(O)₀₋₂ cycloalkyl, —S(O)₀₋₂heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d),—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d), whereinalkylene and cycloalkylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, oxo, optionally substituted C₁₋₆ alkyl,—S(O)₀₋₂alkyl, —OR^(d) and —NR^(d)R^(d′);

each R⁶ is independently selected from halo, C₁₋₈ alkyl, aryl,heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, aralkyl,heteroaralkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ aralkyl, —S(O)₀₋₂ heteroaralkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

R^(a), and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl and optionally substitutedheterocycloalkyl; and

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety;

with the proviso that when W² is H, and L is SO₂, then M is notunsubstituted methyl or ethyl

In some embodiments, R¹ and R² are each independently selected from H,C₁₋₈ alkyl, and optionally substituted aryl.

In some embodiments, R¹ and R² are each independently selected from Hand C₁₋₈ alkyl.

In some embodiments, R¹ and R² are H.

In some embodiments, R¹ and R² are each optionally substituted C₁₋₈alkyl (e.g., methyl).

In some embodiments, R¹ is H and R² is optionally substituted C₁₋₈ alkyl(e.g., methyl)

In some embodiments, R¹ is optionally substituted C₁₋₈ alkyl and R² isH.

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting of halogen(e.g., fluorine), hydroxyl, optionally substituted C₁₋₆ alkyl, C₁₋₈alkoxy, —SO₂ alkyl, and —NR^(d)R^(d′).

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with —SO₂ alkyl (e.g.,methylsulfone).

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with hydroxyl

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting of halogen(e.g., fluorine).

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl (e.g., methyl, ethyl, i-propyl, —C₁₋₂alkyl-OH, —C₁₋₂ alkyl-CF₃, —C₁₋₂ alkyl-CHF₂, —C₁₋₂ alkyl-CH₂F, —C₁₋₂alkyl-NR^(d)R^(d′)).

In some embodiments, A is optionally substituted C₁₋₄ alkylene (e.g.,methylene, ethylene, propylene or butylene).

In some embodiments, A is optionally substituted ethylene

In some embodiments, R³ is selected from H, and optionally substitutedC₁₋₈ alkyl.

In some embodiments, R³ is C₁₋₈ alkyl (e.g., —C₁₋₄ alkyl-OR^(d), —C₁₋₄alkyl-NR^(d)R^(d′), or —C₁₋₄ alkyl-C(O)NR^(d)R^(d′)).

In some embodiments, R³ is H.

In some embodiments, R³ is halogen (e.g., fluorine).

In some embodiments, R³ is optionally substituted aryl.

In some embodiments, R³ is optionally substituted heteroaryl.

In some embodiments, L is a bond.

In some embodiments, L is SO₂.

In some embodiments, M is optionally substituted with 1-3 substituents,each of which is independently selected from the group consisting ofhalogen, C₃₋₈ cycloalkyl, —OR^(d), C₁₋₈ haloalkoxy, —S(O)₀₋₂ C₁₋₈ alkyl,—S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂ aralkyl, —S(O)₀₋₂heteroaralkyl), —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′) optionally substituted —C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d).

In some embodiments, M is aralkyl or heteroaralkyl optionallysubstituted on the alkyl moiety.

In some embodiments, M is optionally substituted aryl (e.g., monocyclicaryl).

In some embodiments, M is optionally substituted monocyclic aryl (e.g.,phenyl).

In some embodiments, M is optionally substituted heteroaryl (e.g.,N-containing heteroaryl).

In some embodiments, M is N-containing heteroaryl (e.g., 2-pyrimidyl).

In some embodiments, M is optionally substituted aralkyl (e.g.,monocyclic or bicyclic aralkyl).

In some embodiments, M is optionally substituted monocyclic aralkyl(e.g., benzyl or methylanisole).

In some embodiments, M is optionally substituted bicyclic aralkyl (e.g.,methylnaphthyl).

In some embodiments, M is optionally substituted heteroaralkyl (e.g.,N-containing heteroaralkyl or S-containing heteroaralkyl).

In some embodiments, M is optionally substituted N-containingheteroaralkyl (e.g., methylpyridyl).

In some embodiments, M is optionally substituted S-containingheteroaralkyl (e.g., methylthionyl).

In some embodiments, W² is C₁₋₈ alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′), —C(O)NR^(d)R^(d′).

In some embodiments, W² is C₂₋₈ alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′), —C(O)NR^(d)R^(d′).

In some embodiments, W² is H.

In some embodiments, W² is optionally substituted C₁₋₈ alkyl.

In some embodiments, W² is optionally substituted C₁₋₈ alkyl (e.g.,—CF₃, —CF₂CF₃, or —CH₂CF₃).

In some embodiments, W² is C₁₋₈ alkyl (e.g. methyl or ethyl).

In some embodiments, W² is optionally substituted aralkyl (e.g.,benzyl).

In some embodiments, each R⁶ is selected from halogen, C₁₋₈ alkyl,hydroxyl, —C₁₋₈ fluoroalkyl, C₁₋₈ haloalkoxy, and —NR^(d)R^(d′).

In some embodiments, each R⁶ is selected from halogen, hydroxyl, —C₁₋₈fluoroalkyl, —C₁₋₈ fluoroalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′), aryl, heteroaryl, and C₁₋₈ alkyl.

In some embodiments, each R⁶ is halogen (e.g., fluorine or chlorine).

In some embodiments, each R⁶ is C₁₋₈ alkyl (e.g., methyl).

In some embodiments, each R⁶ is C₁₋₈ fluoroalkyl (e.g., CF₃).

In some embodiments, each R⁶ is C₁₋₈ fluoroalkoxy (e.g., —OCF₃).

In some embodiments, each R⁶ is aryl (e.g., phenyl).

In some embodiments, each R⁶ is heteroaryl (e.g., pyridine).

In some embodiments, each R⁶ is heterocyclyl further substituted witharyl.

In some embodiments, each R⁶ is heterocyclyl further substituted withheteroaryl.

In some embodiments, a compound of Formula IX is enantiomericallyenriched (e.g., having an ee >60%, >70%, >80%, >90%, >95%, >97%, >98% or>99%).

In some embodiments, the compound is selected from:

-   2-(6-fluoro-4-methoxy-1-(phenylsulfonyl)-1H-indol-3-yl)-N,N-dimethylethanamine,-   2-(1-benzyl-4-(benzyloxy)-7-fluoro-1H-indol-3-yl)-N,N-dimethylethanamine,-   2-(6-fluoro-4-methoxy-1-(pyrimidin-2-yl)-1H-indol-3-yl)-N,N-dimethylethanamine,-   2-(4-(benzyloxy)-7-fluoro-1-(4-methoxybenzyl)-1H-indol-3-yl)-N,N-dimethylethanamine,-   3-(2-(dimethylamino)ethyl)-7-fluoro-1-(4-methoxybenzyl)-1H-indol-4-ol,-   2-(4-(benzyloxy)-7-fluoro-1-(pyridin-2-ylmethyl)-1H-indol-3-yl)-N,N-dimethylethanamine,-   3-(2-(dimethylamino)ethyl)-7-fluoro-1-(pyridin-2-ylmethyl)-1H-indol-4-ol,-   2-(4-(benzyloxy)-7-fluoro-1-(naphthalen-2-ylmethyl)-1H-indol-3-yl)-N,N-dimethylethanamine,-   3-(2-(dimethylamino)ethyl)-7-fluoro-1-(naphthalen-2-ylmethyl)-1H-indol-4-ol,-   2-(4-(benzyloxy)-7-fluoro-1-(thiophen-2-ylmethyl)-1H-indol-3-yl)-N,N-dimethylethanamine,    and-   1-benzyl-3-(2-(dimethylamino)ethyl)-7-fluoro-1H-indol-4-ol.

In another aspect, the invention is directed to a compound selected fromformula:

g is 1, 2 or 3;

R³ is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, halogen, orC(O)NR^(d)R^(d′);

W² is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocycloalkyl, or—C(O)NR^(d)R^(d′);

Q′ is selected from is aryl, heteroaryl, aralkyl, heterocycloalkyl orheteroaralkyl, wherein Q′ is optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, C₃₋₈ cycloalkyl, —OR^(d), C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂aralkyl, —S(O)₀₋₂ heteroaralkyl), —S(O)₀₋₂ cycloalkyl, —S(O)₀₋₂heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted —C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O);

R⁴ is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, —S(O)₂ alkyl, —S(O)₂ heteroalkyl, —S(O)₂ aryl, —S(O)₂heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂ heterocyclyl, —S(O)₂heterocycloalkyl, —S(O)₂ aralkyl, —S(O)₂ heteroaralkyl, —S(O)₂cycloalkyalkyl, formyl, —OR^(d), —NR^(d)R^(d′), —C(O)OR^(a),—C(O)NR^(d)R^(d′), —S(O)₂NR^(d)R^(d′), C₃₋₈ cycloalkyl, heterocyclyl,cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl, aralkyl, andheteroaralkyl, wherein the alkyl, cycloalkyl and heterocyclyl areoptionally substituted with 1-3 substituents, halo, alkyl, haloalkyl,heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryl and herteroarylare optionally substituted with 1-3 substituents, each of which isindependently selected from the group consisting of halogen, alkyl,heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂-aralkyl, —S(O)₀₋₂-heteroaralkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —OR^(d), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d);

each R⁶ is independently selected from halo, C₁₋₈ alkyl, aryl,heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, aralkyl,heteroaralkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ aralkyl, —S(O)₀₋₂ heteroaralkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″)NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

R^(a), and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl and optionally substitutedheterocycloalkyl;

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety.

In some embodiments, R³ is selected from H, and optionally substitutedC₁₋₈ alkyl.

In some embodiments, R³ is C₁₋₈ alkyl (e.g., —C₁₋₄ alkyl-OR^(d), —C₁₋₄alkyl-NR^(d)R^(d′), or —C₁₋₄ alkyl-C(O)NR^(d)R^(d′)).

In some embodiments, R³ is H.

In some embodiments, R³ is halogen (e.g., fluorine).

In some embodiments, R³ is optionally substituted aryl.

In some embodiments, R³ is optionally substituted heteroaryl.

In some embodiments, R⁴ is selected from C₁₋₈ alkyl, aryl, heteroaryl,aralkyl, heteroaralkyl, —S(O)₂ alkyl, —S(O)₂ aralkyl, —S(O)₂heteroaralkyl, —S(O)₂ aryl, —S(O)₂ heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂heterocycloalkyl, —S(O)₂ heterocycloalkylalkyl, and —S(O)₂cycloalkylalkyl.

In some embodiments, R⁴ is selected from C₁₋₈ alkyl (e.g., methyl orethyl).

In some embodiments, R⁴ is selected from C₁₋₈ alkyl, optionallysubstituted with 1-3 fluorine substituents (e.g., —CF₃, —C₁-alkyl-CF₃,—C₁-alkyl-CHF₂, —C₁-alkyl-CH₂F).

In some embodiments, W² is C₁₋₈ alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′), —C(O)NR^(d)R^(d′).

In some embodiments, W² is C₂₋₈ alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′), —C(O)NR^(d)R^(d′).

In some embodiments, W² is H.

In some embodiments, W² is optionally substituted C₁₋₈ alkyl.

In some embodiments, W² is optionally substituted C₁₋₈ alkyl (e.g.,—CF₃, —CF₂CF₃, or —CH₂CF₃).

In some embodiments, W² is C₁₋₈ alkyl (e.g. methyl or ethyl).

In some embodiments, W² is optionally substituted aralkyl (e.g.,benzyl).

In some embodiments, g is 1.

In some embodiments, g is 2.

In some embodiments, each R⁶ is selected from halogen, C₁₋₈ alkyl,hydroxyl, —C₁₋₈ fluoroalkyl, C₁₋₈ haloalkoxy, and —NR^(d)R^(d′).

In some embodiments, each R⁶ is selected from halogen, hydroxyl, —C₁₋₈fluoroalkyl, —C₁₋₈ fluoroalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′), aryl, heteroaryl, and C₁₋₈ alkyl.

In some embodiments, each R⁶ is halogen (e.g., fluorine or chlorine).

In some embodiments, each R⁶ is C₁₋₈ alkyl (e.g., methyl).

In some embodiments, each R⁶ is C₁₋₈ fluoroalkyl (e.g., CF₃).

In some embodiments, each R⁶ is C₁₋₈ fluoroalkoxy (e.g., —OCF₃).

In some embodiments, each R⁶ is aryl (e.g., phenyl).

In some embodiments, each R⁶ is heteroaryl (e.g., pyridine).

In some embodiments, each R⁶ is heterocyclyl further substituted witharyl.

In some embodiments, each R⁶ is heterocyclyl further substituted withheteroaryl.

In some embodiments, a compound of Formula XII is enantiomericallyenriched (e.g., having an ee >60%, >70%, >80%, >90%, >95%, >97%, >98% or>99%).

In some embodiments, Q′ is optionally substituted aryl (e.g., monocyclicaryl).

In some embodiments, Q′ is optionally substituted monocyclic aryl (e.g.,phenyl).

In some embodiments, the compound is2-(5-bromo-1-ethyl-7-fluoro-4-methoxy-1H-indol-3-yl)-N-phenylacetamide.

In some aspects, the invention is directed to a compound selected fromformula:

g is 1, 2 or 3;

is an optionally substituted N-containing heterocyclyl or optionallysubstituted N-containing heteroaryl;

A² is a bond or and optionally substituted C₁₋₄ alkylene;

R³ is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, halogen, orC(O)NR^(d)R^(d′);

W² is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocycloalkyl, or—C(O)NR^(d)R^(d′);

R⁴ is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, —S(O)₂ alkyl, —S(O)₂ heteroalkyl, —S(O)₂ aryl, —S(O)₂heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂ heterocyclyl, —S(O)₂heterocycloalkyl, —S(O)₂ aralkyl, —S(O)₂ heteroaralkyl, —S(O)₂cycloalkyalkyl, formyl, —OR^(d), —NR^(d)R^(d′), —C(O)OR^(a),—C(O)NR^(d)R^(d′), —S(O)₂NR^(d)R^(d′), C₃₋₈ cycloalkyl, heterocyclyl,cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl, aralkyl, andheteroaralkyl, wherein the alkyl, cycloalkyl and heterocyclyl areoptionally substituted with 1-3 substituents, halo, alkyl, haloalkyl,heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryl and herteroarylare optionally substituted with 1-3 substituents, each of which isindependently selected from the group consisting of halogen, alkyl,heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂-aralkyl, —S(O)₀₋₂-heteroaralkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —OR^(d), NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d);

each R⁶ is independently selected from halo, C₁₋₈ alkyl, aryl,heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, aralkyl,heteroaralkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ aralkyl, —S(O)₀₋₂ heteroaralkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

R^(a) and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl and optionally substitutedheterocycloalkyl, or when taken together with the nitrogen atom to whichthey are attached, R^(a) and R^(b) form a 4-8 membered heterocyclicmoiety;

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety.

In some embodiments, A² is optionally substituted C₁₋₄ alkylene (e.g.,methylene or ethylene).

In some embodiments, R³ is selected from H, and optionally substitutedC₁₋₈ alkyl.

In some embodiments, R³ is C₁₋₈ alkyl (e.g., —C₁₋₄ alkyl-OR^(d), —C₁₋₄alkyl-NR^(d)R^(d′), or —C₁₋₄ alkyl-C(O)NR^(d)R^(d′)).

In some embodiments, R³ is H.

In some embodiments, R³ is halogen (e.g., fluorine).

In some embodiments, R³ is optionally substituted aryl.

In some embodiments, R³ is optionally substituted heteroaryl.

In some embodiments, R⁴ is selected from C₁₋₈ alkyl, aryl, heteroaryl,aralkyl, heteroaralkyl, —S(O)₂ alkyl, —S(O)₂ aralkyl, —S(O)₂heteroaralkyl, —S(O)₂ aryl, —S(O)₂ heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂heterocycloalkyl, —S(O)₂ heterocycloalkylalkyl, and —S(O)₂cycloalkylalkyl.

In some embodiments, R⁴ is selected from C₁₋₈ alkyl (e.g., methyl orethyl).

In some embodiments, R⁴ is selected from C₁₋₈ alkyl, optionallysubstituted with 1-3 fluorine substituents (e.g., —CF₃, —C₁-alkyl-CF₃,—C₁-alkyl-CHF₂, —C₁-alkyl-CH₂F).

In some embodiments, W² is C₁₋₈ alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′), —C(O)NR^(d)R^(d′).

In some embodiments, W² is C₂₋₈ alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′), —C(O)NR^(d)R^(d′).

In some embodiments, W² is H.

In some embodiments, W² is optionally substituted C₁₋₈ alkyl.

In some embodiments, W² is optionally substituted C₁₋₈ alkyl (e.g.,—CF₃, —CF₂CF₃, or —CH₂CF₃).

In some embodiments, W² is C₁₋₈ alkyl (e.g. methyl or ethyl).

In some embodiments, W² is optionally substituted aralkyl (e.g.,benzyl).

In some embodiments, g is 1.

In some embodiments, g is 2.

In some embodiments, each R⁶ is selected from halogen, C₁₋₈ alkyl,hydroxyl, —C₁₋₈ fluoroalkyl, C₁₋₈ haloalkoxy, and —NR^(d)R^(d′).

In some embodiments, each R⁶ is selected from halogen, hydroxyl, —C₁₋₈fluoroalkyl, —C₁₋₈ fluoroalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′), aryl, heteroaryl, and C₁₋₈ alkyl.

In some embodiments, each R⁶ is halogen (e.g., fluorine or chlorine).

In some embodiments, each R⁶ is C₁₋₈ alkyl (e.g., methyl).

In some embodiments, each R⁶ is C₁₋₈ fluoroalkyl (e.g., CF₃).

In some embodiments, each R⁶ is C₁₋₈ fluoroalkoxy (e.g., —OCF₃).

In some embodiments, each R⁶ is aryl (e.g., phenyl).

In some embodiments, each R⁶ is heteroaryl (e.g., pyridine).

In some embodiments, each R⁶ is heterocyclyl further substituted witharyl.

In some embodiments, each R⁶ is heterocyclyl further substituted withheteroaryl.

In some embodiments, a compound of Formula XIII is enantiomericallyenriched (e.g., having an ee >60%, >70%, >80%, >90%, >95%, >97%, >98% or>99%).

In some embodiments,

is 3-14 membered (e.g., 4-14 membered, or 5-8 membered) heteroaryl orheterocyclyl.

In some embodiments,

is optionally substituted:

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

is optionally substituted on a carbon and/or nitrogen.

In some embodiments, the compound is selected from:

-   3-(benzo[d]oxazol-2-ylmethyl)-1-ethyl-6-fluoro-1H-indol-4-ol,-   4-(2-(7-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethyl)morpholine,-   3-((1H-benzo[d]imidazol-2-yl)methyl)-1-ethyl-6-fluoro-1H-indol-4-ol,-   1-ethyl-6-fluoro-3-(2-morpholinoethyl)-1H-indol-4-ol,-   1-ethyl-6-fluoro-3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol, and-   7-fluoro-4-methoxy-1-methyl-3-(2-(pyrrolidin-1-yl)ethyl)-1H-indole.

In another aspect, the invention is directed to a compound selected fromformula:

g is 1, 2 or 3;

R¹ and R² are each independently selected from H, C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aralkyl, optionally substituted heteroaralkyl, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocycloalkyl orwhen taken together with the nitrogen atom to which they are attached,R¹ and R² form a 3-8 membered heterocyclic moiety or when taken togetherwith the nitrogen atom to which they are attached R¹ or R² and A form anoptionally substituted 4-8 membered heterocyclyl or heteroaryl moiety;

R³ is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, halogen, orC(O)NR^(d)R^(d′);

W² is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocycloalkyl, or—C(O)NR^(d)R^(d′);

A is optionally substituted C₁₋₄ alkylene, optionally substitutedcycloalkylene, optionally substituted arylene, optionally substitutedheteroarylene, optionally substituted heterocycloalkylene whereinarylene or heteroarylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, C₃₋₈ cycloalkyl, —OR^(d), C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂aralkyl, —S(O)₀₋₂ heteroaralkyl), —S(O)₀₋₂ cycloalkyl, —S(O)₀₋₂heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d), whereinalkylene and cycloalkylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, oxo, optionally substituted C₁₋₆ alkyl,—S(O)₀₋₂alkyl, —OR^(d) and —NR^(d)R^(d′);

R⁴ is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, —S(O)₂ alkyl, —S(O)₂ heteroalkyl, —S(O)₂ aryl, —S(O)₂heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂ heterocyclyl, —S(O)₂heterocycloalkyl, —S(O)₂ aralkyl, —S(O)₂ heteroaralkyl, —S(O)₂cycloalkyalkyl, formyl, —OR^(d), —NR^(d)R^(d′), —C(O)OR^(a),—C(O)NR^(d)R^(d′), —S(O)₂NR^(d)R^(d′), C₃₋₈ cycloalkyl, heterocyclyl,cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl, aralkyl, andheteroaralkyl, wherein the alkyl, cycloalkyl and heterocyclyl areoptionally substituted with 1-3 substituents, halo, alkyl, haloalkyl,heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryl and herteroarylare optionally substituted with 1-3 substituents, each of which isindependently selected from the group consisting of halogen, alkyl,heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂-aralkyl, —S(O)₀₋₂-heteroaralkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —OR^(d), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′) optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d);

each R⁶ is independently selected from halo, C₁₋₈ alkyl, aryl,heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, aralkyl,heteroaralkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ aralkyl, —S(O)₀₋₂ heteroaralkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

R^(a) and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl and optionally substitutedheterocycloalkyl;

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety.

In some embodiments, R¹ and R² are each independently selected from H,C₁₋₈ alkyl, and optionally substituted aryl.

In some embodiments, R¹ and R² are each independently selected from Hand C₁₋₈ alkyl.

In some embodiments, R¹ and R² are H.

In some embodiments, R¹ and R² are each optionally substituted C₁₋₈alkyl (e.g., methyl).

In some embodiments, R¹ is H and R² is optionally substituted C₁₋₈ alkyl(e.g., methyl)

In some embodiments, R¹ is optionally substituted C₁₋₈ alkyl and R² isH.

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting of halogen(e.g., fluorine), hydroxyl, optionally substituted C₁₋₆ alkyl, C₁₋₈alkoxy, —SO₂ alkyl, and —NR^(d)R^(d′).

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with —SO₂ alkyl (e.g.,methylsulfone).

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with hydroxyl

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting of halogen(e.g., fluorine).

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl (e.g., methyl, ethyl, i-propyl, —C₁₋₂alkyl-OH, —C₁₋₂ alkyl-CF₃, —C₁₋₂ alkyl-CHF₂, —C₁₋₂ alkyl-CH₂F, —C₁₋₂alkyl-NR^(d)R^(d′)).

In some embodiments, A is optionally substituted C₁₋₄ alkylene (e.g.,methylene, ethylene, propylene or butylene).

In some embodiments, A is selected from optionally substituted ethylene(e.g.,

In some embodiments, R³ is selected from H, and optionally substitutedC₁₋₈ alkyl.

In some embodiments, R³ is optionally substituted C₁₋₈ alkyl (e.g.,—C₁₋₄ alkyl-OR^(d), —C₁₋₄ alkyl-NR^(d)R^(d′), or —C₁₋₄alkyl-C(O)NR^(d)R^(d′)).

In some embodiments, R³ is H.

In some embodiments, R³ is halogen (e.g., fluorine).

In some embodiments, R³ is optionally substituted aryl.

In some embodiments, R³ is optionally substituted heteroaryl.

In some embodiments, R⁴ is selected from C₁₋₈ alkyl, aryl, heteroaryl,aralkyl, heteroaralkyl, —S(O)₂ alkyl, —S(O)₂ aralkyl, —S(O)₂heteroaralkyl, —S(O)₂ aryl, —S(O)₂ heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂heterocycloalkyl, —S(O)₂ heterocycloalkylalkyl, and —S(O)₂cycloalkylalkyl.

In some embodiments, R⁴ is selected from C₁₋₈ alkyl (e.g., methyl orethyl).

In some embodiments, R⁴ is selected from C₁₋₈ alkyl, optionallysubstituted with 1-3 fluorine substituents (e.g., —CF₃, —C₁-alkyl-CF₃,—C₁-alkyl-CHF₂, —C₁-alkyl-CH₂F).

In some embodiments, W² is C₁₋₈ alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′), —C(O)NR^(d)R^(d′).

In some embodiments, W² is C₂₋₈ alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′), —C(O)NR^(d)R^(d′).

In some embodiments, W² is H.

In some embodiments, W² is optionally substituted C₁₋₈ alkyl.

In some embodiments, W² is optionally substituted C₁₋₈ alkyl (e.g.,—CF₃, —CF₂CF₃, or —CH₂CF₃).

In some embodiments, W² is C₁₋₈ alkyl (e.g. methyl or ethyl).

In some embodiments, W² is optionally substituted aralkyl (e.g.,benzyl).

In some embodiments, g is 1.

In some embodiments, g is 2.

In some embodiments, each R⁶ is selected from halogen, C₁₋₈ alkyl,hydroxyl, —C₁₋₈ fluoroalkyl, C₁₋₈ haloalkoxy, and —NR^(d)R^(d′).

In some embodiments, each R⁶ is selected from halogen, hydroxyl, —C₁₋₈fluoroalkyl, —C₁₋₈ fluoroalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′), aryl, heteroaryl, and C₁₋₈ alkyl.

In some embodiments, each R⁶ is halogen (e.g., fluorine or chlorine).

In some embodiments, each R⁶ is C₁₋₈ alkyl (e.g., methyl).

In some embodiments, each R⁶ is C₁₋₈ fluoroalkyl (e.g., CF₃).

In some embodiments, each R⁶ is C₁₋₈ fluoroalkoxy (e.g., —OCF₃).

In some embodiments, each R⁶ is aryl (e.g., phenyl).

In some embodiments, each R⁶ is heteroaryl (e.g., pyridine).

In some embodiments, each R⁶ is heterocyclyl further substituted witharyl.

In some embodiments, each R⁶ is heterocyclyl further substituted withheteroaryl.

In some embodiments, a compound of Formula XIV is enantiomericallyenriched (e.g., having an ee >60%, >70%, >80%, >90%, >95%, >97%, >98% or>99%).

In some embodiments, the compound is2-(6-(benzyloxy)-5-fluoro-1H-indol-3-yl)-N,N-dimethylethanamine.

In another aspect, the invention is directed to a compound selected fromformula:

wherein

g is 1, 2 or 3;

R¹ and R² are each independently selected from H, C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aralkyl, optionally substituted heteroaralkyl, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocycloalkyl orwhen taken together with the nitrogen atom to which they are attached,R¹ and R² form a 3-8 membered heterocyclic moiety or when taken togetherwith the nitrogen atom to which they are attached R¹ or R² and A form anoptionally substituted 4-8 membered heterocyclyl or heteroaryl moiety;

W² is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocycloalkyl, or—C(O)NR^(d)R^(d′);

A is optionally substituted C₁₋₄ alkylene, optionally substitutedcycloalkylene, optionally substituted arylene, optionally substitutedheteroarylene, wherein arylene or heteroarylene are optionallysubstituted with 1-3 substituents, each of which is independentlyselected from the group consisting of halogen, C₃₋₈ cycloalkyl, —OR^(d),C₁₋₈ haloalkoxy, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ aralkyl, —S(O)₀₋₂ heteroaralkyl),—OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(a),—NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl,—NR^(d)S(O)₂cycloalkyl, —NR^(d)S(O)₂heterocycloalkyl,—NR^(d)S(O)₂-aralkyl, —NR^(d)S(O)₂—C₁₋₄alkyl-heteroaryl,—NR^(d)S(O)₂—C₁₋₄alkyl-cycloalkyl,—NR^(d)S(O)₂—C₁₋₄alkyl-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′) optionally substituted—C₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d),wherein alkylene and cycloalkylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of fluorine, oxo, optionally substituted C₁₋₆ alkyl,—S(O)₀₋₂alkyl, —OR^(d) and —NR^(d)R^(d′);

R⁴ is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, —S(O)₂ alkyl, —S(O)₂ heteroalkyl, —S(O)₂ aryl, —S(O)₂heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂ heterocyclyl, —S(O)₂heterocycloalkyl, —S(O)₂ aralkyl, —S(O)₂ heteroaralkyl, —S(O)₂cycloalkyalkyl, formyl, —OR^(d), —NR^(d)R^(d′), —C(O)OR^(a),—C(O)NR^(d)R^(d′), —S(O)₂NR^(d)R^(d′), C₃₋₈ cycloalkyl, heterocyclyl,cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl, aralkyl, andheteroaralkyl, wherein the alkyl, cycloalkyl and heterocyclyl areoptionally substituted with 1-3 substituents, halo, alkyl, haloalkyl,heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryl and heteroaryl areoptionally substituted with 1-3 substituents, each of which isindependently selected from the group consisting of halogen, alkyl,heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂-aralkyl, —S(O)₀₋₂-heteroaralkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —OR^(d), NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d);

each R⁶ is independently selected from halo, C₁₋₈ alkyl, aryl,heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, aralkyl,heteroaralkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ aralkyl, —S(O)₀₋₂ heteroaralkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

R^(a) and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl and optionally substitutedheterocycloalkyl;

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety.

In some embodiments, R¹ and R² are each independently selected from H,C₁₋₈ alkyl, and optionally substituted aryl.

In some embodiments, R¹ and R² are each independently selected from Hand C₁₋₈ alkyl.

In some embodiments, R¹ and R² are H.

In some embodiments, R¹ and R² are each optionally substituted C₁₋₈alkyl (e.g., methyl).

In some embodiments, R¹ is H and R² is optionally substituted C₁₋₈ alkyl(e.g., methyl)

In some embodiments, R¹ is optionally substituted C₁₋₈ alkyl and R² isH.

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting of halogen(e.g., fluorine), hydroxyl, optionally substituted C₁₋₆ alkyl, C₁₋₈alkoxy, —SO₂ alkyl, and —NR^(d)R^(d′).

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with —SO₂ alkyl (e.g.,methylsulfone).

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with hydroxyl

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting of halogen(e.g., fluorine).

In some embodiments, A is optionally substituted C₁₋₄ alkylene, whereinthe C₁₋₄ alkylene is optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl (e.g., methyl, ethyl, i-propyl, —C₁₋₂alkyl-OH, —C₁₋₂ alkyl-CF₃, —C₁₋₂ alkyl-CHF₂, —C₁₋₂ alkyl-CH₂F, —C₁₋₂alkyl-NR^(d)R^(d′)).

In some embodiments, A is optionally substituted C₁₋₄ alkylene (e.g.,methylene, ethylene, propylene or butylene).

In some embodiments, A is optionally substituted ethylene

In some embodiments, R⁴ is selected from C₁₋₈ alkyl, aryl, heteroaryl,aralkyl, heteroaralkyl, —S(O)₂ alkyl, —S(O)₂ aralkyl, —S(O)₂heteroaralkyl, —S(O)₂ aryl, —S(O)₂ heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂heterocycloalkyl, —S(O)₂ heterocycloalkylalkyl, and —S(O)₂cycloalkylalkyl.

In some embodiments, R⁴ is selected from C₁₋₈ alkyl (e.g., methyl orethyl).

In some embodiments, R⁴ is selected from C₁₋₈ alkyl, optionallysubstituted with 1-3 fluorine substituents (e.g., —CF₃, —C₁ alkyl-CF₃,—C₁ alkyl-CHF₂, —C₁ alkyl-CH₂F).

In some embodiments, W² is C₁₋₈ alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′), —C(O)NR^(d)R^(d′).

In some embodiments, W² is C₂₋₈ alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′), —C(O)NR^(d)R^(d′).

In some embodiments, W² is H.

In some embodiments, W² is optionally substituted C₁₋₈ alkyl.

In some embodiments, W² is optionally substituted C₁₋₈ alkyl (e.g.,—CF₃, —CF₂CF₃, or —CH₂CF₃).

In some embodiments, W² is C₁₋₈ alkyl (e.g. methyl or ethyl).

In some embodiments, W² is optionally substituted aralkyl (e.g.,benzyl).

In some embodiments, g is 1.

In some embodiments, g is 2.

In some embodiments, each R⁶ is selected from halogen, C₁₋₈ alkyl,hydroxyl, —C₁₋₈ fluoroalkyl, C₁₋₈ haloalkoxy, and —NR^(d)R^(d′).

In some embodiments, each R⁶ is selected from halogen, hydroxyl, —C₁₋₈fluoroalkyl, —C₁₋₈ fluoroalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′), aryl, heteroaryl, and C₁₋₈ alkyl.

In some embodiments, each R⁶ is halogen (e.g., fluorine or chlorine).

In some embodiments, each R⁶ is C₁₋₈ alkyl (e.g., methyl).

In some embodiments, each R⁶ is C₁₋₈ fluoroalkyl (e.g., CF₃).

In some embodiments, each R⁶ is C₁₋₈ fluoroalkoxy (e.g., —OCF₃).

In some embodiments, each R⁶ is aryl (e.g., phenyl).

In some embodiments, each R⁶ is heteroaryl (e.g., pyridine).

In some embodiments, each R⁶ is heterocyclyl further substituted witharyl.

In some embodiments, each R⁶ is heterocyclyl further substituted withheteroaryl.

In some embodiments, a compound of Formula XV is enantiomericallyenriched (e.g., having an ee >60%, >70%, >80%, >90%, >95%, >97%, >98% or>99%).

In some embodiments, the compound is of the following formula:

In another aspect, the invention is directed to a compound selected fromformula:

wherein

g is 1, 2 or 3;

R³ is selected from H, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclyl, halogen, orC(O)NR^(d)R^(d′);

W² is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, optionally substitutedheteroaralkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocycloalkyl, or—C(O)NR^(d)R^(d′);

A³ is C₂₋₈ branched alkylene;

R⁴ is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, —S(O)₂ alkyl, —S(O)₂ heteroalkyl, —S(O)₂ aryl, —S(O)₂heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂ heterocyclyl, —S(O)₂heterocycloalkyl, —S(O)₂ aralkyl, —S(O)₂ heteroaralkyl, —S(O)₂cycloalkyalkyl, formyl, —OR^(d), C₁₋₈ aryloxy, C₁₋₈ heteroaryloxy,—NR^(d)R^(d′), C₁₋₈ alkylamino, di(C₁₋₈ alkyl)amino, —C(O)OR^(a),—C(O)NR^(d)R^(d′), —S(O)₂NR^(d)R^(d′), C₃₋₈ cycloalkyl, heterocyclyl,cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl, aralkyl, andheteroaralkyl, wherein the alkyl, cycloalkyl and heterocyclyl areoptionally substituted with 1-3 substituents, halo, alkyl, haloalkyl,heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryl and herteroarylare optionally substituted with 1-3 substituents, each of which isindependently selected from the group consisting of halogen, alkyl,heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂-aralkyl, —S(O)₀₋₂-heteroaralkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —OR^(d), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d);

each R⁶ is independently selected from halo, C₁₋₈ alkyl, aryl,heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, aralkyl,heteroaralkyl, cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈haloalkoxy, C₁₋₈ haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ aralkyl, —S(O)₀₋₂ heteroaralkyl, —S(O)₀₋₂cycloalkyl, —S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl,—S(O)₀₋₂ cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-aralkyl,—NR^(d)S(O)₂-heteroaralkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted;

R¹³ is selected from hydrogen and methyl; and

R^(a) and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted cycloalkylalkyl and optionally substitutedheterocycloalkyl;

R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety.

In some embodiments, A³ is 1-methylethylene.

In some embodiments, A³ is

In some embodiments, R³ is selected from H, and optionally substitutedC₁₋₈ alkyl.

In some embodiments, R³ is C₁₋₈ alkyl (e.g., —C₁₋₄ alkyl-OR^(d), —C₁₋₄alkyl-NR^(d)R^(d′), or —C₁₋₄ alkyl-C(O)NR^(d)R^(d′)).

In some embodiments, R³ is H.

In some embodiments, R³ is halogen (e.g., fluorine).

In some embodiments, R³ is optionally substituted aryl.

In some embodiments, R³ is optionally substituted heteroaryl.

In some embodiments, R⁴ is selected from C₁₋₈ alkyl, aryl, heteroaryl,aralkyl, heteroaralkyl, —S(O)₂ alkyl, —S(O)₂ aralkyl, —S(O)₂heteroaralkyl, —S(O)₂ aryl, —S(O)₂ heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂heterocycloalkyl, —S(O)₂ heterocycloalkylalkyl, and —S(O)₂cycloalkylalkyl.

In some embodiments, R⁴ is selected from C₁₋₈ alkyl (e.g., methyl orethyl).

In some embodiments, R⁴ is selected from C₁₋₈ alkyl, optionallysubstituted with 1-3 fluorine substituents (e.g., —CF₃, —C₁-alkyl-CF₃,—C₁-alkyl-CHF₂, —C₁-alkyl-CH₂F).

In some embodiments, W² is C₁₋₈ alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′), —C(O)NR^(d)R^(d′).

In some embodiments, W² is C₂₋₈ alkyl optionally substituted with—OR^(d), —NR^(d)R^(d′), —C(O)NR^(d)R^(d′).

In some embodiments, W² is H.

In some embodiments, W² is optionally substituted C₁₋₈ alkyl.

In some embodiments, W² is optionally substituted C₁₋₈ alkyl (e.g.,—CF₃, —CF₂CF₃, or —CH₂CF₃).

In some embodiments, W² is C₁₋₈ alkyl (e.g. methyl or ethyl).

In some embodiments, W² is optionally substituted aralkyl (e.g.,benzyl).

In some embodiments, g is 1.

In some embodiments, g is 2.

In some embodiments, each R⁶ is selected from halogen, C₁₋₈ alkyl,hydroxyl, —C₁₋₈ fluoroalkyl, C₁₋₈ haloalkoxy, and —NR^(d)R^(d′).

In some embodiments, each R⁶ is selected from halogen, hydroxyl, —C₁₋₈fluoroalkyl, —C₁₋₈ fluoroalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′), aryl, heteroaryl, and C₁₋₈ alkyl.

In some embodiments, each R⁶ is halogen (e.g., fluorine or chlorine).

In some embodiments, each R⁶ is C₁₋₈ alkyl (e.g., methyl).

In some embodiments, each R⁶ is C₁₋₈ fluoroalkyl (e.g., CF₃).

In some embodiments, each R⁶ is C₁₋₈ fluoroalkoxy (e.g., —OCF₃).

In some embodiments, each R⁶ is aryl (e.g., phenyl).

In some embodiments, each R⁶ is heteroaryl (e.g., pyridine).

In some embodiments, each R⁶ is heterocyclyl further substituted witharyl.

In some embodiments, each R⁶ is heterocyclyl further substituted withheteroaryl.

In some embodiments, the compounds is2-(7-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)propan-1-amine.

In some embodiments, a compound of Formula XVI is enantiomericallyenriched (e.g., having an ee >60%, >70%, >80%, >90%, >95%, >97%, >98% or>99%).

In one aspect, the invention features a pharmaceutical compositioncomprising a compound of formulae I, II, IV, VII, VIII, IX, XII, XIII,XIV, XV or XVI.

In one aspect, the invention features a dosage form comprising acompound of formulae I, II, IV, VII, VIII, IX, XII, XIII, XIV, XV orXVI. In some embodiments, the dosage form is an oral dosage form.

In one aspect, the invention features a method for the treatment ofobesity in a subject, the method comprising administering to the subjecta compound as described herein, such that obesity is treated.

In one aspect, the invention features a method for the treatment ofObsessive Compulsive Disorder (OCD) in a subject, the method comprisingadministering to the subject a compound as described herein, such thatOCD is treated.

In one aspect, the invention features a method for suppressing appetitein a subject, the method comprising administering to the subject acompound as described herein, such that appetite is suppressed in thesubject.

In one aspect, the invention features a method for the treatment ofobesity in a subject, the method comprising administering to the subjecta compound as described herein, such that obesity is treated.

In one aspect, the invention features a method for the treatment ofschizophrenia or psychosis in a subject, the method comprisingadministering to the subject a compound as described herein, such thatschizophrenia or psychosis is treated.

In one aspect, the invention features a method for the treatment ofanxiety or depression in a subject, the method comprising administeringto the subject a compound as described herein, such that anxiety ordepression is treated in the subject.

In one aspect, the invention features a method for the treatment ofdiabetes in a subject, the method comprising administering to thesubject a compound as described herein, such that diabetes is treated inthe subject.

In one aspect, the invention features a method for the treatment ofattention deficit hyperactivity disorder (ADHD) in a subject, the methodcomprising administering to the subject a compound as described herein,such that ADHD is treated in the subject.

In one aspect, the invention features a method for the treatment ofsuicidal behavior in a subject, the method comprising administering tothe subject a compound as described herein, such that suicidal behavioris treated in the subject.

In one aspect, the invention features a method for the treatment ofmigraine in a subject, the method comprising administering to thesubject a compound as described herein, such that migraine is treated inthe subject.

In one aspect, the invention features a method for enhancing cognition(e.g., treating cognitive deficiency) in a subject, the methodcomprising administering to the subject a compound as described herein,such that cognition is enhanced in the subject.

In one aspect, the invention features a method for treating bipolardisorder in a subject, the method comprising administering to thesubject a compound as described herein, such that bipolar disorder istreated in the subject.

In one aspect, the invention features a method for the treatment of acentral nervous system disorder in a subject, the method comprisingadministering to the subject a compound as described herein, such thatthe central nervous system disorder is treated. In some embodiments, thecentral nervous system disorder is selected from the group consisting ofepilepsy, Alzheimer's disease, sexual dysfunction, addiction, anorexianervosa, Tourette's syndrome, and trichotillomania.

In one aspect, the invention features a method for the treatment ofacral lick dermatitis (ALD) in a canine subject, the method comprisingadministering to the subject a compound as described herein, such thatacral lick dermatitis is treated.

In one aspect, the invention features a method of modulating (e.g.,inhibit or activate) a serotonin receptor (e.g., a 5-HT receptor), themethod comprising contacting a serotonin receptor with a compound offormulae I, II, IV, VII, VIII, IX, XII, XIII, XIV, XV or XVI. In someembodiments, the invention features a method of inhibiting a 5-HTreceptor. In some embodiments, the invention features a method ofactivating a 5-HT receptor. In some embodiments, the invention featuresa method of modulating (e.g., inhibiting or activating) a 5-HT_(2A)receptor. In some embodiments, the invention features a method ofmodulating (e.g., inhibiting or activating) a 5-HT_(2C) receptor. Insome embodiments, the invention features a method of modulating (e.g.,inhibiting or activating) a 5-HT₆ receptor. In some embodiments, thecompound is selective towards a 5-HT_(2A) receptor. In some embodiments,the compound is selective toward a 5-HT_(2C) receptor. In someembodiments, the compound is selective toward a 5-HT₆ receptor.

DETAILED DESCRIPTION 1. Definitions

Before further description of the present invention, and in order thatthe invention may be more readily understood, certain terms are firstdefined and collected here for convenience.

The term “acyl” refers to an alkylcarbonyl, cycloalkylcarbonyl,arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent,any of which may be further substituted (e.g., by one or moresubstituents).

The term “alkenyl” refers to a straight or branched hydrocarbon chaincontaining 2-12 carbon atoms (unless otherwise noted) and having one ormore double bonds. Examples of alkenyl groups include, but are notlimited to, alyl, propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups.One of the double bond carbons may optionally be the point of attachmentof the alkenyl substituent.

The term “alkenylene” refers to a divalent alkenyl, e.g. —CH═CH—,—CH₂—CH═CH—, and —CH═CH—CH₂—.

The term “alkynyl” refers to a straight or branched hydrocarbon chaincontaining 2-12 carbon atoms (unless otherwise noted) and characterizedin having one or more triple bonds. Examples of alkynyl groups include,but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of thetriple bond carbons may optionally be the point of attachment of thealkynyl substituent.

The term “alkynylene” refers to a divalent alkynyl, e.g. —CH═CH—,—CH₂—CH═CH—, and —CH═CH—CH₂—.

The terms “alkoxyl” or “alkoxy” as used herein refers to an alkyl group,as defined below, having an oxygen radical attached thereto.Representative alkoxy groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. The term “alkoxyalkyl” refers to an alkyl inwhich one or more hydrogen atoms are replaced by an alkoxy group.

An “ether” is two hydrocarbons covalently linked by an oxygen.

The term “alkyl” refers to the radical of saturated aliphatic groups,including straight-chain alkyl groups, and branched-chain alkyl groups.In preferred embodiments, a straight chain or branched chain alkyl has12 or fewer carbon atoms in its backbone (unless otherwise noted) e.g.,from 1-12, 1-8, 1-6, or 1-4. Exemplary alkyl moieties include methyl,ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl,isobutyl or t-butyl), pentyl (e.g., n-pentyl, isopentyl or pentan-3-yl),hexyl and hepty.

The term “alkylene” refers to a divalent alkyl, e.g., —CH₂—, —CH₂CH₂—,and —CH₂CH₂CH₂—.

The term “alkoxylene” refers to an alkylene wherein a CH₂ is substitutedwith an oxygen. For example, an aryl alkoxylene refers to a group withan alkylene attached to an aryl group through an oxygen, an optionallysubstituted heteroaryl alkoxylene refers to a group with an alkyleneattached to an heteroaryl group through an oxygen.

The term “amino” refers to —NH₂.

The terms “alkylamino” and “dialkylamino” refer to —NH(alkyl) and—N(alkyl)₂ radicals respectively.

The term “aralkylamino” refers to a —NH(aralkyl) radical. The termalkylaminoalkyl refers to a (alkyl)NH-alkyl-radical; the termdialkylaminoalkyl refers to a (alkyl)₂N-alkyl-radical.

The term “amido” refers to a —NHC(O)— or C(O)NH₂ substituent.

The term “aryl” refers to a 6-carbon monocyclic, 10-carbon bicyclic, or14-carbon tricyclic aromatic ring system wherein 0, 1, 2, 3, or 4 atomsof each ring may be substituted by a substituent. Examples of arylmoieties include, but are not limited to, phenyl, naphthyl and the like.The term “arylalkyl” refers to alkyl substituted with an aryl. Exemplaryaralkyls include but are not limited to benzyl, 1-phenylethyl,2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, phenethyl, andtrityl groups. The term “arylalkenyl” refers to an alkenyl substitutedwith an aryl. The term “arylalkynyl” refers to an alkynyl substitutedwith an aryl. Terms such as “arylC₂-C₆alkyl” are to be read as a furtherlimitation on the size of the alkyl group. The term “arylalkoxy” refersto an alkoxysubstituted with aryl. The term “arylenyl” refers to adivalent aryl (i.e., —Ar—).

The terms “cycloalkyl” or “cyclyl” as employed herein include saturatedand partially unsaturated cyclic hydrocarbon groups having 3 to 12carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons,wherein the cycloalkyl group may be optionally substituted. Exemplarycyclyl groups include, without limitation, cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, andcyclooctyl. Cyclyl moieties also include both bridged and fused ringsystems. Cyclyl groups also include those that are fused to additionalring systems, which may be saturated or unsaturated. A cyclyl group maythus be a bicyclic group in which one ring is saturated or partiallyunsaturated and the other is fully unsaturated (e.g., indanyl).

The term “cyclylalkyl” as used herein, refers to an alkyl groupsubstituted with a cyclyl group. Cyclylalkyl includes groups in whichmore than one hydrogen atom of an alkyl group has been replaced by acyclyl group.

The term “cycloalkylalkyl” as used herein, refers to an alkyl groupsubstituted with a cycloalkyl group.

The term “halo” or “halogen” refers to any radical of fluorine,chlorine, bromine or iodine.

The term “haloalkyl” refers to an alkyl group that may have any numberof hydrogens available on the group replaced with a halogen atom.Representative haloalkyl groups include but are not limited to: —CH₂Cl,—CH₂ClCF₃, —CHBr₂, —CF₃, —CH₂F, —CHF₂, and —CH₂CF₃. The term“fluoroalkyl” refers to an alkyl group that may have any number ofhydrogens available on the group replaced with a fluorine atom.Representative fluoroalkyl groups include but are not limited to: —CH₂F,—CH₂FCF₃, —CHF₂ or —CF₃. The term “haloalkoxy” refers to an alkoxy groupthat may have any number of hydrogen atoms available on the alkyl groupreplaced with a halogen atom. Representative haloalkoxy groups includebut are not limited to: —OCH₂Cl, —OCH₂ClCF₃, —OCHBr₂, —OCHF₂ or —OCF₃.The term “fluoroalkoxy” refers to an alkoxy group that may have anynumber of hydrogens available on the group replaced with a fluorineatom. Representative fluoroalkoxy groups include but are not limited to:—OCH₂F, —OCH₂FCF₃, —OCHF₂ or —OCF₃.

The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system having1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S(e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S ifmonocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3,or 4 atoms of each ring may be substituted by a substituent. Examples ofheteroaryl groups include pyridyl, furyl or furanyl, imidazolyl,benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, quinolinyl, indolyl,thiazolyl, oxazolyl and the like. The term “heteroarylalkyl” or the term“heteroaralkyl” refers to an alkyl substituted with a heteroaryl. Theterm “heteroarylalkenyl” refers to an alkenyl substituted with aheteroaryl. The term “heteroarylalkynyl” refers to an alkynylsubstituted with a heteroaryl. The term “heteroarylalkoxy” refers to analkoxy substituted with heteroaryl.

The term “heteroaryl” refers to a group having 5 to 14 ring atoms,preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 π electronsshared in a cyclic array; and having, in addition to carbon atoms, fromone to five heteroatoms. A heteroaryl group may be mono-, bi-, tri-, orpolycyclic, preferably mono-, bi-, or tricyclic, more preferably mono-or bicyclic. When a heteroaryl is substituted by a hydroxy group, italso includes its corresponding tautomer. The term “heteroaryl,” as usedherein, also includes groups in which a heteroaromatic ring is fused toone or more aryl rings. Nonlimiting examples of heteroaryl groupsinclude thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Theterm “heteroaryl” may be used interchangeably with the terms “heteroarylring”, “heteroaryl group,” or “heteroaromatic,” any of which termsinclude rings that are optionally substituted. A ring nitrogen atom of aheteroaryl may be oxidized to form the corresponding N-oxide compound. Anonlimiting example of such a heteroaryl having an oxidized ringnitrogen atom is N-oxopyridyl.

The term “heteroarylalkyl” refers to an alkyl group substituted by aheteroaryl. Heteroarylalkyl includes groups in which more than onehydrogen atom has been replaced by a heteroaryl group.

As used herein, the terms “heterocycle,” “heterocyclyl” and“heterocyclic ring” are used interchangeably and refer to a stable 3- to8-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety thatis either saturated or partially unsaturated, and having, in addition tocarbon atoms, one or more, preferably one to four, heteroatoms, asdefined above. When used in reference to a ring atom of a heterocycle,the term “nitrogen” includes a substituted nitrogen. As an example, in asaturated or partially unsaturated ring having 0-3 heteroatoms selectedfrom oxygen, sulfur or nitrogen, the nitrogen may be N (as in3,4-dihydro-2/y-pyrrolyl), NH (as in pyrrolidinyl), or NR⁺ (as inN-substituted pyrrolidinyl). A heterocyclic ring can be attached to itspendant group at any heteroatom or carbon atom that results in a stablestructure and any of the ring atoms can be optionally substituted.Examples of such saturated or partially unsaturated heterocyclicradicals include, without limitation, tetrahydrofuranyl,tetrahydropyranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl,oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl,thiazepinyl, morpholinyl, and thiomorpholinyl. A heterocyclyl group maybe mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic,more preferably mono- or bicyclic. Additionally, a heterocyclic ringalso includes groups in which the heterocyclyl ring is fused to one ormore aryl, heteroaryl or cyclyl rings. A ring nitrogen atom of aheterocyclic ring also may be oxidized to form the correspondingN-hydroxy compound.

The term “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl. Heterocyclylalkyl includes groups in which more than onehydrogen atom has been replaced by a heterocyclyl group.

In the case of arylalkyl, heteroarylalkyl, cyclylalkyl,heterocyclylalkyl etc. The terms “hetaralkyl” and “heteroaralkyl”, asused herein, refers to an alkyl group substituted with a heteroarylgroup. Exemplary heteroaralkyl groups include but are not limited tomethylpyridyl or methylpyrimidyl.

The term “heterocyclyl” or “heterocyclylalkyl” refers to a nonaromatic5-8 membered monocyclic, 5-12 membered bicyclic, or 11-14 memberedtricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, saidheteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6,or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic,respectively), wherein 0, 1, 2 or 3 atoms of each ring may besubstituted by a substituent. Examples of heterocyclyl groups includepiperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, andinclude both bridged and fused ring systems. The term“heterocyclylalkyl” refers to an alkyl substituted with a heterocyclyl.

The term “heterocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a heterocycle group.

The term “heteroalkyl,” as used herein, refers to a saturate orunsaturated, straight or branched chain aliphatic group, wherein one ormore of the carbon atoms in the chain are independently replaced by aheteroatom. Exemplary heteroatoms include O, S, and N.

Aralkyl, heteroalkyl, etc groups described as optionally substituted, itis intended that either or both aryl, alkyl or heteroraryl and alkyl maybe independent optionally substituted or unsubstituted.

The term “hydroxyalkyl” refers to an alkyl in which one or more hydrogenatoms are replaced by a hydroxy group.

The term “oxo” refers to an oxygen atom (═O), which forms a carbonylwhen attached to carbon, an N-oxide when attached to nitrogen, and asulfoxide or sulfone when attached to sulfur.

The term “thioalkyl” as used herein refers to an —S(alkyl) group, wherethe point of attachment is through the sulfur atom and the alkyl groupis as defined above.

The term “thiono” refers to a sulfur atom (═S), which forms a thioketonewhen attached to carbon.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more carbons of the backbone. It will be understoodthat “substitution” or “substituted with” includes the implicit provisothat such substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and non-aromaticsubstituents of organic compounds. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this invention, the heteroatoms such as nitrogen mayhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms.

The term “substituent” refers to a group “substituted” on a moietydescribed herein. Any atom on any substituent can be substituted.Substituents can include any substituents described herein. Exemplarysubstituents include, without limitation, alkyl (e.g., C1, C2, C3, C4,C5, C6, C7, C8, C9, C10, C11, C12 straight or branched chain alkyl),cycloalkyl, haloalkyl (e.g., perfluoroalkyl such as CF₃), aryl,heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl, alkynyl,cycloalkenyl, heterocycloalkenyl, alkoxy, haloalkoxy (e.g.,perfluoroalkoxy such as OCF₃), halo, hydroxy, carboxy, carboxylate,cyano, nitro, amino, alkyl amino, SO₃H, sulfate, phosphate,methylenedioxy (—O—CH₂—O— wherein oxygens are attached to vicinalatoms), ethylenedioxy, oxo, thioxo (e.g., C═S), imino (alkyl, aryl,aralkyl), S(O)_(n)alkyl (where n is 0-2), S(O)_(n) aryl (where n is0-2), S(O)_(n) heteroaryl (where n is 0-2), S(O)_(n) heterocyclyl (wheren is 0-2), amine (mono-, di-, alkyl, cycloalkyl, aralkyl, heteroaralkyl,aryl, heteroaryl, and combinations thereof), ester (alkyl, aralkyl,heteroaralkyl, aryl, heteroaryl), amide (mono-, di-, alkyl, aralkyl,heteroaralkyl, aryl, heteroaryl, and combinations thereof), sulfonamide(mono-, di-, alkyl, aralkyl, heteroaralkyl, and combinations thereof).In one aspect, the substituents on a group are independently any onesingle, or any subset of the aforementioned substituents. In anotheraspect, a substituent may itself be substituted with any one of theabove substituents.

As used herein, the phrase “optionally substituted” is usedinterchangeably with the phrase “substituted or unsubstituted.” Ingeneral, the term “substituted”, whether preceded by the term“optionally” or not, means that a hydrogen radical of the designatedmoiety is replaced with the radical of a specified substituent, providedthat the substitution results in a stable or chemically feasiblecompound. The term “substitutable”, when used in reference to adesignated atom, means that attached to the atom is a hydrogen radical,which hydrogen atom can be replaced with the radical of a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a substituent at each substitutable position of thegroup, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds.

As used herein, the term “optionally substituted” means substituted orunsubstituted.

The term “administration” or “administering” includes routes ofintroducing the compound(s) of the invention to a subject to performtheir intended function. Examples of routes of administration that maybe used include injection (subcutaneous, intravenous, parenterally,intraperitoneally, intrathecal), oral, inhalation, rectal andtransdermal. The pharmaceutical preparations may be given by formssuitable for each administration route. For example, these preparationsare administered in tablets or capsule form, by injection, inhalation,eye lotion, ointment, suppository, etc. administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral administration is preferred. The injection can bebolus or can be continuous infusion. Depending on the route ofadministration, a compound described herein can be coated with ordisposed in a selected material to protect it from natural conditionswhich may detrimentally affect its ability to perform its intendedfunction. A compound or composition described herein can be administeredalone, or in conjunction with either another agent as described above orwith a pharmaceutically-acceptable carrier, or both. A compound orcomposition described herein can be administered prior to theadministration of the other agent, simultaneously with the agent, orafter the administration of the agent. Furthermore, a compound describedherein can also be administered in a pro-drug form which is convertedinto its active metabolite, or more active metabolite in vivo.

The language “biological activities” of a compound described hereinincludes all activities elicited by a compound described herein in aresponsive subject or cell. It includes genomic and non-genomicactivities elicited by these compounds.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner. With respect to the nomenclature of a chiral center,terms “R” and “S” configuration are as defined by the IUPACRecommendations. As to the use of the terms, diastereomer, racemate,epimer and enantiomer will be used in their normal context to describethe stereochemistry of preparations.

The term “diastereomers” refers to stereoisomers with two or morecenters of dissymmetry and whose molecules are not mirror images of oneanother.

An “effective amount” or “an amount effective” refers to an amount ofthe compound or composition which is effective, upon single or multipledose administrations to a subject and for periods of time necessary, intreating a cell, or curing, alleviating, relieving or improving asymptom of a disorder, e.g., a disorder described herein. An effectiveamount of a compound described herein may vary according to factors suchas the disease state, age, and weight of the subject, and the ability ofa compound described herein to elicit a desired response in the subject.Dosage regimens may be adjusted to provide the optimum therapeuticresponse. An effective amount is also one in which any toxic ordetrimental effects (e.g., side effects) of a compound described hereinare outweighed by the therapeutically beneficial effects. The term“effective amount” includes an amount effective, at dosages and forperiods of time necessary, to achieve the desired result, e.g., suppressappetite in a subject and/or treat a disorder described herein such as aserotonin receptor related disorder. Exemplary disorders includeobesity; a disorder wherein appetite suppression is desirable; adisorder in which treating weight gain is desirable; a disorder in whichcognitive enhancement is desirable; depressive disorders (e.g.,depression, atypical depression, major depressive disorder, dysthymicdisorder, and substance-induced mood disorder); bipolar disorders (e.g.,bipolar I disorder, bipolar II disorder, and cyclothymic disorder);anxiety disorders (e.g., panic attack, agoraphobia, panic disorder,specific phobia, social phobia, obsessive compulsive disorder,posttraumatic stress disorder, acute stress disorder, generalizedanxiety disorder, separation anxiety disorder, and substance-inducedanxiety disorder); mood episodes (e.g., major depressive episode, manicepisode, mixed episode, and hypomanic episode); adjustment disorders(e.g., adjustment disorder with anxiety and/or depressed mood);intellectual deficit disorders (e.g., dementia, Alzheimer's disease, andmemory deficit); eating disorders (e.g., hyperphagia, bulimia oranorexia nervosa); schizophrenia (e.g., paranoid type, disorganizedtype, catatonic type, and undifferentiated type); schizophreniformdisorder, schizoaffective disorder, delusional disorder, other psychoticdisorders (e.g., substance-induced psychotic disorder, L-DOPA-inducedpsychosis, psychosis associated with Alzheimer's dementia, psychosisassociated with Parkinson's disease, psychosis associated with Lewy bodydisease); sleep disorders (e.g., sleep apnea); suicidal behaviors;sexual dysfunction; migraine; cephalic pain or other pain; raisedintracranial pressure; epilepsy; personality disorders; age-relatedbehavioral disorders; behavioral disorders associated with dementia;organic mental disorders; mental disorders in childhood; aggressivity;age-related memory disorders; chronic fatigue syndrome; addiction (e.g.,drug and alcohol addiction); premenstrual tension; damage of the centralnervous system such as by trauma, stroke, neurodegenerative diseases ortoxic or infective CNS diseases such as encephalitis or meningitis;cardiovascular disorders (e.g., thrombosis); hypertension;hyperlipidemia; arterial constriction; osteoarthritis; gall bladderdisease; gout; gastrointestinal disorders (e.g., dysfunction ofgastrointestinal motility); diabetes mellitus (e.g., Type 2 diabetesmellitus) and diabetes insipidus; cancer; infertility; early mortality;spinal cord injuries; Tourette's syndrome; trichotillomania; othercentral nervous system disorders; attention deficit hyperactivitydisorder (ADHD); canine veterinary diseases (e.g., acral lickdermatitis); and combinations of these disorders that may be present ina mammal.

An effective amount of a compound described herein may vary according tofactors such as the disease state, age, and weight of the subject, andthe ability of a compound described herein to elicit a desired responsein the subject. Dosage regimens may be adjusted to provide the optimumtherapeutic response. An effective amount is also one in which any toxicor detrimental effects (e.g., side effects) of a compound describedherein are outweighed by the therapeutically beneficial effects.

A therapeutically effective amount of a compound described herein (i.e.,an effective dosage) may range from about 0.001 to 50 mg/kg body weight,preferably about 0.01 to 40 mg/kg body weight, more preferably about 0.1to 35 mg/kg body weight, still more preferably about 1 to 30 mg/kg, andeven more preferably about 10 to 30 mg/kg. The skilled artisan willappreciate that certain factors may influence the dosage required toeffectively treat a subject, including but not limited to the severityof the disease or disorder, previous treatments, the general healthand/or age of the subject, and other diseases present. Moreover,treatment of a subject with a therapeutically effective amount of acompound described herein can include a single treatment or, preferably,can include a series of treatments. In one example, a subject is treatedwith a compound described herein in the range of between about 0.1 to 20mg/kg body weight, one time per week for between about 1 to 10 weeks,preferably between 2 to 8 weeks, more preferably between about 3 to 7weeks, and even more preferably for about 4, 5, or 6 weeks. It will alsobe appreciated that the effective dosage of a compound described hereinused for treatment may increase or decrease over the course of aparticular treatment.

As used herein, an amount of a compound effective to prevent a disorder,or “a prophylactically effective amount” of the compound refers to anamount effective, upon single- or multiple-dose administration to thesubject, in preventing or delaying the occurrence of the onset orrecurrence of a disorder or a symptom of the disorder.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen,sulfur, phosphorus and silicon. A heteroatom may be present in anyoxidation state (e.g., any oxidized form of nitrogen, sulfur, phosphorusor silicon) and any charged state (e.g., the quaternized form of anybasic nitrogen), and includes a substitutable nitrogen of a heterocyclicring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl).

The term “enantiomers” refers to two stereoisomers of a compound whichare non-superimposable mirror images of one another. An equimolarmixture of two enantiomers is called a “racemic mixture” or a“racemate.”

The term “isomers” or “stereoisomers” refers to compounds which haveidentical chemical constitution, but differ with regard to thearrangement of the atoms or groups in space. For example, isomersinclude cis- and trans-isomers, E- and Z-isomers, R- and S-enantiomers,diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, andother mixtures thereof.

The language “improved biological properties” refers to any activityinherent in a compound described herein that enhances its effectivenessin vivo. In a preferred embodiment, this term refers to any qualitativeor quantitative improved therapeutic property of a compound describedherein, such as reduced off-target effects.

The term “modulate” refers to an increase or decrease, e.g., in theactivity of a serotonin receptor in response to exposure to a compounddescribed herein, e.g., the stimulation of serotonin receptor activityof at least a sub-population of cells in an animal such that a desiredend result is achieved, e.g., a therapeutic result. In some embodiments,a compound as described herein is an inhibitor of a serotonin receptordescribed herein.

As used herein, the term “partially unsaturated” refers to a moiety thatincludes at least one double or triple bond between atoms. The term“partially unsaturated” encompasses rings, e.g., having one or moresites of unsaturation, but that are not completely unsaturated so as tobe aryl or heteroaryl.

As used herein, the term “subject” is intended to include human andnon-human animals. Exemplary human subjects include a human patienthaving a disorder, e.g., a disorder described herein, or a normalsubject. The term “non-human animals” includes all vertebrates, e.g.,non-mammals (such as chickens, amphibians, reptiles) and mammals, suchas non-human primates, domesticated and/or agriculturally usefulanimals, e.g., sheep, dog, cat, cow, pig, etc.

As used herein, the term “treat” or “treating” is defined as applying oradministering a compound or composition, alone or in combination with asecond compound or composition, to a subject, e.g., a patient, orapplying or administering the compound or composition to an isolatedtissue or cell, e.g., cell line, from a subject, e.g., a patient, whohas a disorder (e.g., a disorder as described herein), a symptom of adisorder, or a predisposition toward a disorder, with the purpose tocure, heal, alleviate, relieve, alter, remedy, ameliorate, improve oraffect the disorder, one or more symptoms of the disorder or thepredisposition toward the disorder (e.g., to prevent at least onesymptom of the disorder or to delay onset of at least one symptom of thedisorder).

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The term “prodrug” or “pro-drug” includes compounds with moieties thatcan be metabolized in vivo. Generally, the prodrugs are metabolized invivo by esterases or by other mechanisms to active drugs. Examples ofprodrugs and their uses are well known in the art (See, e.g., Berge etal. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19). The prodrugscan be prepared in situ during the final isolation and purification ofthe compounds, or by separately reacting the purified compound in itsfree acid form or hydroxyl with a suitable esterifying agent. Hydroxylgroups can be converted into esters via treatment with a carboxylicacid. Examples of prodrug moieties include substituted andunsubstituted, branch or unbranched lower alkyl ester moieties, (e.g.,propionoic acid esters), lower alkenyl esters, di-lower alkyl-aminolower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino loweralkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters(e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-loweralkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo,or methoxy substituents) aryl and aryl-lower alkyl esters, amides,lower-alkyl amides, di-lower alkyl amides, and hydroxy amides. Preferredprodrug moieties are propionoic acid esters and acyl esters. Prodrugswhich are converted to active forms through other mechanisms in vivo arealso included.

The term “Positron Emission Tomography isotope,” “PET isotope,” and “PETtracer” may be used interchangeably to describe one or more isotopesthat are known to be detectable using positron emission tomography. Suchisotopes may include any positron-creating radioisotope that can beincorporated into a compound, thus allowing imaging of the delivery,metabolism, etc., of a compound of the invention. Exemplary isotopesinclude ¹¹C, ³N, ¹⁵O, and ¹⁸F. The compounds and methods of theinvention are intended to broadly include the substitution of one ormore natural isotopes in the compounds with PET isotopes.

The language “a prophylactically effective amount” of a compound refersto an amount of a compound described herein any formula herein orotherwise described herein which is effective, upon single or multipledose administration to the patient, in preventing or treating a diseaseor condition.

The language “reduced off-target effects” is intended to include areduction in any undesired side effect elicited by a compound describedherein when administered in vivo. In some embodiments, a compounddescribed herein has little to no cardio and/or pulmonary toxicity(e.g., when administered to a subject). In some embodiments, a compounddescribed herein has little to no hallucinogenic activity (e.g., whenadministered to a subject).

The term “selective” means a greater activity against a first target(e.g., a 5-HT receptor subtype) relative to a second target (e.g., asecond 5-HT receptor subtype). In some embodiments a compound has aselectivity of at least 1.25-fold, at least 1.5 fold, at least 2-fold,at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, atleast 10-fold or at least 100-fold greater towards a first targetrelative to a second target. In some embodiments, a compound describedherein is selective towards the 5-HT_(2A) receptor relative to one ormore other 5-HT receptor subtypes such as 5-HT_(2C) and/or 5-HT₆. Insome embodiments, a compound described herein is selective towards the5-HT_(2C) receptor relative to one or more other 5-HT receptor subtypessuch as 5-HT_(2A) and/or 5-HT₆. In some embodiments, a compounddescribed herein is selective towards the 5-HT₆ receptor relative to oneor more other 5-HT receptor subtypes such as 5-HT_(2A) and/or 5-HT_(2C).

The term “subject” includes organisms which are capable of sufferingfrom a serotonin-receptor-related disorder or who could otherwisebenefit from the administration of a compound described herein of theinvention, such as human and non-human animals. Preferred humans includehuman patients suffering from or prone to suffering from aserotonin-related disorder or associated state, as described herein. Theterm “non-human animals” of the invention includes all vertebrates,e.g., mammals, e.g., rodents, e.g., mice, and non-mammals, such asnon-human primates, e.g., sheep, dog, cow, chickens, amphibians,reptiles, etc.

The phrases “systemic administration,” “administered systemically”,“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound described herein(s), drugor other material, such that it enters the patient's system and, thus,is subject to metabolism and other like processes, for example,subcutaneous administration.

2. Compounds of the Invention

The compounds described herein (e.g., a compound of formula I, II, IV,VII, VIII, IX, XII, XIII, XIV, XV, or XVI) can be used for a variety oftherapeutic purposes, including the modulation of a 5-HT receptor andcan be used, for example to inhibit or activate a 5-HT receptor in asubject. For example 5-HT_(2A), 5-HT_(2C) and/or 5-HT₆.

Exemplary compounds include compounds of formulae I, II, IV, VII, VIII,IX, XII, XIII, XIV, XV, and XVI as shown below. The substituents asprovided in compounds I, II, IV, VII, VIII, IX, XII, XIII, XIV, XV, andXVI are as defined above. Exemplary compounds also include the tablesand Examples disclosed herein.

The compounds of the invention can be prepared by a variety of methods,including those known in the art or apparent to the skilled artisan inlight of the present specification. For example, N-unsubstituted indolescan be N-alkylated, for example, with an alkyl halide, using a base suchas sodium hydride, to give N-alkylated indoles. 4-substituted indolescan be hydrogenated using, for example, palladium hydroxide on carbon ascatalyst in the presence of hydrogen gas, to give 4-hydroxyindoles.4-hydroxyindoles can be O-alkylated, for example, with an alkyl halide,using a base such as sodium hydride, to give 4-O-alkoxy-N-substitutedindoles. N-unsubstituted indoles can be prepared starting from3-fluoro-2-benzyloxy benzaldehyde via cyclization of a intermediatestyrylazide to the ester, followed by hydrolysis, with for example,sodium hydroxide, decarboxylation using as example a copper catalyst and2-phenylpyridine, oxamidation with oxalyl chloride followed by asecondary amine, and then reduction.

The present invention includes compounds that differ only in thepresence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays.

In the compounds of the present invention, any atom not specificallydesignated as a particular isotope is meant to represent any stableisotope of that atom unless otherwise stated (e.g., hydrogen, H² ordeuterium and H³ or tritium). The formulas described herein may or maynot indicate whether atoms at certain positions are isotopicallyenriched. When a structural formula is silent with respect to whether aparticular position is isotopically enriched, it is to be understoodthat the isotopes at that particular position are present in naturalabundance or, that the particular position is isotopically enriched withone or more naturally occurring stable isotopes. For example, theformula —CH₂— represents the following possible structures: —CH₂—, —CHD-or —CD₂-.

The variable “D” is defined as deuterium.

The terms “compound” or “compounds,” when referring to a compound ofthis invention or a compound described herein, refers to a collection ofmolecules having an identical chemical structure, except that there maybe isotopic variation among the constituent atoms of the molecules.Thus, it will be clear to those of skill in the art that a compoundrepresented by a particular chemical structure containing indicatedhydrogen atoms will contain lesser amounts of isotopologues havingdeuterium atoms at one or more of the designated hydrogen positions inthat structure. Alternatively, a compound represented by a particularchemical structure containing indicated deuterium atoms will containlesser amounts of isotopologues having hydrogen atoms at one or more ofthe designated deuterium positions in that structure. The relativeamount of such isotopologues in a compound of this invention will dependon a number of factors including isotopic purity of deuterated reagentsused to make the compound and the efficiency of incorporation ofdeuterium in the various synthetic steps used to prepare the compound.The relative amount of such isotopologues in total will be less than 55%of the compound. In other embodiments, the relative amount of suchisotopologues in total will be less than 50%, less than 45%, less than40%, less than 35%, less than 35%, less than 15%, less than 10%, lessthan 5%, less than 1% or less than 0.5% of the compound.

The term “isotopologue” refers to a species that differs from a specificcompound of this invention only in the isotopic composition thereof.Isotopologues can differ in the level of isotopic enrichment at one ormore positions and/or in the position(s) of isotopic enrichment.

The compounds of this invention may contain one or more asymmetriccenters and thus occur as racemates and racemic mixtures, singleenantiomers, individual diastereomers and diastereomeric mixtures.Described herein are enantiomerically enriched compounds (e.g., acompound resolved to an enantiomeric excess of 60%, 70%, 80%, 85%, 90%,95%, 99% or greater). All such isomeric forms of these compounds areexpressly included in the present invention. The compounds of thisinvention may also contain linkages (e.g., carbon-carbon bonds) orsubstituents that can restrict bond rotation, e.g. restriction resultingfrom the presence of a ring or double bond. Accordingly, all cis/transand E/Z isomers are expressly included in the present invention. Thecompounds of this invention may also be represented in multipletautomeric forms, in such instances, the invention expressly includesall tautomeric forms of the compounds described herein, even though onlya single tautomeric form may be represented (e.g., alkylation of a ringsystem may result in alkylation at multiple sites, the inventionexpressly includes all such reaction products). All such isomeric formsof such compounds are expressly included in the present invention. Allcrystal forms of the compounds described herein are expressly includedin the present invention.

Naturally occurring or synthetic isomers can be separated in severalways known in the art. Methods for separating a racemic mixture of twoenantiomers include chromatography using a chiral stationary phase (see,e.g., “Chiral Liquid Chromatography,” W. J. Lough, Ed. Chapman and Hall,New York (1989)). Enantiomers can also be separated by classicalresolution techniques. For example, formation of diastereomeric saltsand fractional crystallization can be used to separate enantiomers. Forthe separation of enantiomers of carboxylic acids, the diastereomericsalts can be formed by addition of enantiomerically pure chiral basessuch as brucine, quinine, ephedrine, strychnine, and the like.Alternatively, diastereomeric esters can be formed with enantiomericallypure chiral alcohols such as menthol, followed by separation of thediastereomeric esters and hydrolysis to yield the free, enantiomericallyenriched carboxylic acid. For separation of the optical isomers of aminocompounds, addition of chiral carboxylic or sulfonic acids, such ascamphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid canresult in formation of the diastereomeric salts. For example a compoundcan be resolved to an enantiomeric excess (e.g., 60%, 70%, 80%, 85%,90%, 95%, 99% or greater) via formation of diasteromeric salts, e.g.with a chiral base, e.g., (+) or (−)-methylbenzylamine, or via highperformance liquid chromatography using a chiral column. In someembodiments a product is purified directly on a chiral column to provideenantiomerically enriched compound.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

3. Uses of the Compounds of the Invention

As described herein below, it has now surprisingly been found that thecompounds of the invention have serotonin receptor activity, and can beused to treat or prevent conditions associated with serotonin receptoractivity. In some embodiments, a compound described herein has agonistactivity against a 5-HT receptor with an EC₅₀ of ≦10 μM.

Thus, in one embodiment, the invention provides methods for treating asubject for a serotonin-receptor-related disorder (i.e., a 5-HT receptorrelated disorder), or preventing a serotonin-receptor-related disorder(i.e., a 5-HT receptor related disorder), by administering to thesubject an effective amount of a compound described herein, such thatthe serotonin-receptor-related disorder is treated or prevented.

Fourteen distinct 5-HT receptor subtypes exist in seven separatefamilies. There is particular interest in the three receptor subtypes ofthe 5-HT₂ family, e.g., 5-HT_(2A), 5-HT_(2C), and/or 5-HT₆. In someembodiments, a compound described herein is selective for a particularsubtype (e.g., 5-HT_(2A), 5-HT_(2C) or 5-HT₆). For example, a compounddescribed herein, when administered in vitro or in vivo, has an activityof at least 1.25-fold higher against 5-HT_(2A) over another subtype suchas 5-HT_(2C) or 5-HT₆ (e.g., at least 1.25-fold, at least 1.5 fold, atleast 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, atleast 6-fold, at least 10-fold or at least 100-fold). In anotherexample, a compound described herein, when administered in vitro or invivo, has an activity of at least 1.25-fold higher against 5-HT_(2C)over another subtype such as 5-HT_(2A) or 5-HT₆ (e.g., at least1.25-fold, at least 1.5 fold, at least 2-fold, at least 3-fold, at least4-fold, at least 5-fold, at least 6-fold, at least 10-fold or at least100-fold). In another example, a compound described herein, whenadministered in vitro or in vivo, has an activity of at least 1.25-foldhigher against 5-HT₆ over another subtype such as 5-HT_(2A) or 5-HT_(2C)(e.g., at least 1.25-fold, at least 1.5 fold, at least 2-fold, at least3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least10-fold or at least 100-fold). In some embodiments a compound describedherein has agonist activity against 5-HT_(2A) with an EC₅₀ of ≦10 μM. Insome embodiments, a compound described herein has agonist activityagainst 5-HT_(2C) with an EC₅₀ of ≦10 μM. In some embodiments, acompound described herein has agonist activity against 5-HT₆ with anEC₅₀ of ≦10 μM.

Thus, a compound described herein may be used in the treatment orprevention of disorders such as obesity; a disorder wherein appetitesuppression is desirable; a disorder in which treating weight gain isdesirable; a disorder in which cognitive enhancement is desirable;depressive disorders (e.g., depression, atypical depression, majordepressive disorder, dysthymic disorder, and substance-induced mooddisorder); bipolar disorders (e.g., bipolar I disorder, bipolar IIdisorder, and cyclothymic disorder); anxiety disorders (e.g., panicattack, agoraphobia, panic disorder, specific phobia, social phobia,obsessive compulsive disorder, posttraumatic stress disorder, acutestress disorder, generalized anxiety disorder, separation anxietydisorder, and substance-induced anxiety disorder); mood episodes (e.g.,major depressive episode, manic episode, mixed episode, and hypomanicepisode); adjustment disorders (e.g., adjustment disorder with anxietyand/or depressed mood); intellectual deficit disorders (e.g., dementia,Alzheimer's disease, and memory deficit); eating disorders (e.g.,hyperphagia, bulimia or anorexia nervosa); schizophrenia (e.g., paranoidtype, disorganized type, catatonic type, and undifferentiated type);schizophreniform disorder, schizoaffective disorder, delusionaldisorder, other psychotic disorders (e.g., substance-induced psychoticdisorder, L-DOPA-induced psychosis, psychosis associated withAlzheimer's dementia, psychosis associated with Parkinson's disease,psychosis associated with Lewy body disease); sleep disorders (e.g.,sleep apnea); suicidal behaviors; sexual dysfunction; migraine; cephalicpain or other pain; raised intracranial pressure; epilepsy; personalitydisorders; age-related behavioral disorders; behavioral disordersassociated with dementia; organic mental disorders; mental disorders inchildhood; aggressivity; age-related memory disorders; chronic fatiguesyndrome; addiction (e.g., drug and alcohol addiction); premenstrualtension; damage of the central nervous system such as by trauma, stroke,neurodegenerative diseases or toxic or infective CNS diseases such asencephalitis or meningitis; cardiovascular disorders (e.g., thrombosis);hypertension; hyperlipidemia; arterial constriction; osteoarthritis;gall bladder disease; gout; gastrointestinal disorders (e.g.,dysfunction of gastrointestinal motility); diabetes mellitus (e.g., Type2 diabetes mellitus) and diabetes insipidus; cancer; infertility; earlymortality; spinal cord injuries; Tourette's syndrome; trichotillomania;other central nervous system disorders; attention deficit hyperactivitydisorder (ADHD); canine veterinary diseases (e.g., acral lickdermatitis); and combinations of these disorders that may be present ina mammal. A compound described herein may also be used to suppressappetite in a subject, to enhance cognition (e.g., treating cognitivedeficiency) in a subject, or treat weight gain in a subject.

In one embodiment, a method of treating a subject suffering from orsusceptible to a serotonin-receptor-related disorder includesadministering to a subject in need thereof a therapeutically effectiveamount of a compound described herein, to thereby treat the subjectsuffering from or susceptible to a serotonin-receptor-related disorder.

A further aspect relates to a method of treating a subject sufferingfrom or susceptible to obesity, including administering to the subjectan effective amount of a compound described herein to thereby treat thesubject suffering from or susceptible to obesity.

A further aspect relates to a method of suppressing appetite in asubject, including administering to the subject an effective amount of acompound described herein to thereby suppress appetite in the subject.

A further aspect relates to treating weight gain in a subject (e.g.,weight gain associated with treatment with another medication),including administering to the subject an effective amount of a compounddescribed herein to thereby treat weight gain in the subject.

A further aspect relates to enhancing cognition in a subject, includingadministering to the subject an effective amount of a compound describedherein to thereby enhance cognition in the subject.

A further aspect relates to treating suicidal behavior in a subject,including administering to the subject an effective amount of a compounddescribed herein to thereby treat suicidal behavior in the subject.

A further aspect relates to a method of treating a subject sufferingfrom or susceptible to Obsessive Compulsive Disorder (OCD), includingadministering to the subject an effective amount of a compound describedherein to thereby treat the subject suffering from or susceptible toOCD.

A further aspect relates to a method of treating a subject sufferingfrom or susceptible to schizophrenia or psychosis, includingadministering to the subject an effective amount of a compound describedherein to thereby treat the subject suffering from or susceptible toschizophrenia or psychosis.

A further aspect relates to a method of treating a subject sufferingfrom or susceptible to anxiety or depression, including administering tothe subject an effective amount of a compound described herein tothereby treat the subject suffering from or susceptible to anxiety ordepression.

A further aspect relates to a method of treating a subject sufferingfrom or susceptible to migraine, including administering to the subjectan effective amount of a compound described herein to thereby treat thesubject suffering from or susceptible to migraine.

In certain embodiments, the methods of the invention includeadministering to a subject a therapeutically effective amount of acompound described herein in combination with another pharmaceuticallyactive compound. Examples of pharmaceutically active compounds includecompounds known to treat serotonin-related diseases. Otherpharmaceutically active compounds that may be used can be found inHarrison's Principles of Internal Medicine, Sixteenth Edition, Eds. D.L. Kasper et al. McGraw-Hill Professional, N.Y., NY (2004); and the 2005Physician's Desk Reference 59th Edition, Thomson Healthcare, 2004, thecomplete contents of which are expressly incorporated herein byreference. A compound described herein and a pharmaceutically activecompound may be administered to the subject in the same pharmaceuticalcomposition or in different pharmaceutical compositions (at the sametime or at different times).

Determination of a therapeutically effective or a prophylacticallyeffective amount of a compound described herein, can be readily made bythe physician or veterinarian (the “attending clinician”), as oneskilled in the art, by the use of known techniques and by observingresults obtained under analogous circumstances. The dosages may bevaried depending upon the requirements of the patient in the judgment ofthe attending clinician; the severity of the condition being treated andthe particular compound being employed. In determining thetherapeutically effective amount or dose, and the prophylacticallyeffective amount or dose, a number of factors are considered by theattending clinician, including, but not limited to: the specificserotonin-receptor-related disorder involved; pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the desired time course of treatment; the species ofmammal; its size, age, and general health; the specific diseaseinvolved; the degree of or involvement or the severity of the disease;the response of the individual patient; the particular compoundadministered; the mode of administration; the bioavailabilitycharacteristics of the preparation administered; the dose regimenselected; the kind of concurrent treatment (i.e., the interaction of acompound described herein with other co-administered therapeutics); andother relevant circumstances.

Treatment can be initiated with smaller dosages, which are less than theoptimum dose of the compound. Thereafter, the dosage may be increased bysmall increments until the optimum effect under the circumstances isreached. For convenience, the total daily dosage may be divided andadministered in portions during the day if desired.

Compounds determined to be effective for the prevention or treatment ofserotonin-receptor-related disorders in animals, e.g., dogs, chickens,and rodents, may also be useful in treatment ofserotonin-receptor-related disorders in humans. Those skilled in the artof treating serotonin-receptor-related disorders in humans will know,based upon the data obtained in animal studies, the dosage and route ofadministration of the compound to humans. In general, the dosage androute of administration in humans is expected to be similar to that inanimals.

The identification of those patients who are in need of prophylactictreatment for serotonin-receptor-related disorders is well within theability and knowledge of one skilled in the art. Certain of the methodsfor identification of patients which are at risk of developingserotonin-receptor-related disorders which can be treated by the subjectmethod are appreciated in the medical arts, such as family history, andthe presence of risk factors associated with the development of thatdisease state in the subject patient. A clinician skilled in the art canreadily identify such candidate patients, by the use of, for example,clinical tests, physical examination and medical/family history.

In another aspect, a compound described herein is packaged in atherapeutically effective amount with a pharmaceutically acceptablecarrier or diluent. The composition may be formulated for treating asubject suffering from or susceptible to a serotonin-receptor-relateddisorder, and packaged with instructions to treat a subject sufferingfrom or susceptible to a serotonin-receptor-related disorder.

In another aspect, the invention provides methods for stimulating orincreasing serotonin receptor activity. In one embodiment, a method ofincreasing serotonin receptor activity (or a serotonin receptor relatedactivity) according to the invention includes contacting cells with acompound capable of increasing serotonin receptor activity. Thecontacting may be in vitro, e.g., by addition of the compound to a fluidsurrounding the cells, for example, to the growth media in which thecells are living or existing. The contacting may also be by directlycontacting the compound to the cells. Alternately, the contacting may bein vivo, e.g., by passage of the compound through a subject; forexample, after administration, depending on the route of administration,the compound may travel through the digestive tract or the blood streamor may be applied or administered directly to cells in need oftreatment.

In another aspect, methods of inhibiting a serotonin-receptor-relateddisorder in a subject include administering an effective amount of acompound described herein (e.g., a compound of any of the formulaeherein capable of increasing serotonin receptor activity) to thesubject. The administration may be by any route of administering knownin the pharmaceutical arts. The subject may have aserotonin-receptor-related disorder, may be at risk of developing aserotonin-receptor-related disorder, or may need prophylactic treatmentprior to anticipated or unanticipated exposure to a conditions capableof increasing susceptibility to a serotonin-receptor-related disorder.

In one aspect, a method of monitoring the progress of a subject beingtreated with a serotonin receptor active compound described hereinincludes determining the pre-treatment status of theserotonin-receptor-related disorder, administering a therapeuticallyeffective amount of a compound described herein to the subject, anddetermining the status of the serotonin-receptor-related disorder afteran initial period of treatment, wherein the modulation (e.g.,improvement) of the status indicates efficacy of the treatment.

In one aspect, methods of selecting a subject suffering from orsusceptible to a serotonin-receptor-related disorder for treatment witha compound described herein comprise determining the pre-treatmentstatus of the serotonin-receptor-related disorder, administering atherapeutically effective amount of a compound described herein to thesubject, and determining the status (of the serotonin-receptor-relateddisorder after an initial period of treatment with the compound, whereinthe modulation (e.g., improvement) of the status is an indication thatthe serotonin-receptor-related disorder is likely to have a favorableclinical response to treatment with a compound described herein.

The subject may be at risk of a serotonin-receptor-related disorder, maybe exhibiting symptoms of a serotonin-receptor-related disorder, may besusceptible to a serotonin-receptor-related disorder and/or may havebeen diagnosed with a serotonin-receptor-related disorder.

The initial period of treatment may be the time in which it takes toestablish a stable and/or therapeutically effective blood serum level ofthe compound, or the time in which it take for the subject to clear asubstantial portion of the compound, or any period of time selected bythe subject or healthcare professional that is relevant to thetreatment.

If the modulation of the status indicates that the subject may have afavorable clinical response to the treatment, the subject may be treatedwith the compound. For example, the subject can be administeredtherapeutically effective dose or doses of the compound.

Kits of the invention include kits for treating aserotonin-receptor-related disorder in a subject. The invention alsoincludes kits for assessing the efficacy of a treatment for aserotonin-receptor-related disorder in a subject, monitoring theprogress of a subject being treated for a serotonin-receptor-relateddisorder, selecting a subject with a serotonin-receptor-related disorderfor treatment according to the invention, and/or treating a subjectsuffering from or susceptible to a serotonin-receptor-related disorder.The kit may include a compound described herein, for example, a compoundof any of formula described herein, pharmaceutically acceptable esters,salts, and prodrugs thereof, and instructions for use. The instructionsfor use may include information on dosage, method of delivery, storageof the kit, etc. The kits may also include reagents, for example, testcompounds, buffers, media (e.g., cell growth media), cells, etc. Testcompounds may include known compounds or newly discovered compounds, forexample, combinatorial libraries of compounds. One or more of the kit ofthe invention may be packaged together, for example, a kit for assessingthe efficacy of a treatment for a serotonin-receptor-related disordermay be packaged with a kit for monitoring the progress of a subjectbeing treated for a serotonin-receptor-related disorder according to theinvention.

Certain of the present methods can be performed on cells in culture,e.g. in vitro or ex vivo, or on cells present in an animal subject,e.g., in vivo. A compound described herein can be initially tested invitro using cells that express a serotonin receptor (see, e.g., theExamples, infra).

Alternatively, the effects of a compound described herein can becharacterized in vivo using animals models.

4. Pharmaceutical Compositions

The invention also provides a pharmaceutical composition, comprising aneffective amount of a compound described herein (e.g., a compoundcapable of treating or preventing a condition as described herein, e.g.,a compound of any formula herein or otherwise described herein) and apharmaceutically acceptable carrier.

In an embodiment, a compound described herein is administered to thesubject using a pharmaceutically-acceptable formulation, e.g., apharmaceutically-acceptable formulation that provides sustained deliveryof a compound described herein to a subject for at least 12 hours, 24hours, 36 hours, 48 hours, one week, two weeks, three weeks, or fourweeks after the pharmaceutically-acceptable formulation is administeredto the subject.

In certain embodiments, these pharmaceutical compositions are suitablefor topical or oral administration to a subject. In other embodiments,as described in detail below, the pharmaceutical compositions of thepresent invention may be specially formulated for administration insolid or liquid form, including those adapted for the following: (1)oral administration, for example, drenches (aqueous or non-aqueoussolutions or suspensions), tablets, boluses, powders, granules, pastes;(2) parenteral administration, for example, by subcutaneous,intramuscular or intravenous injection as, for example, a sterilesolution or suspension; (3) topical application, for example, as acream, ointment or spray applied to the skin; (4) intravaginally orintrarectally, for example, as a pessary, cream or foam; or (5) aerosol,for example, as an aqueous aerosol, liposomal preparation or solidparticles containing the compound.

The phrase “pharmaceutically acceptable” refers to a compound describedherein, compositions containing such compounds, and/or dosage formswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically-acceptable carrier” includespharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting the subject chemical fromone organ, or portion of the body, to another organ, or portion of thebody. Each carrier is “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not injurious to thepatient. Some examples of materials which can serve aspharmaceutically-acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Compositions containing a compound described herein(s) include thosesuitable for oral, nasal, topical (including buccal and sublingual),rectal, vaginal, aerosol and/or parenteral administration. Thecompositions may conveniently be presented in unit dosage form and maybe prepared by any methods well known in the art of pharmacy. The amountof active ingredient which can be combined with a carrier material toproduce a single dosage form will vary depending upon the host beingtreated, the particular mode of administration. The amount of activeingredient which can be combined with a carrier material to produce asingle dosage form will generally be that amount of the compound whichproduces a therapeutic effect. Generally, out of one hundred per cent,this amount will range from about 1 per cent to about ninety-ninepercent of active ingredient, preferably from about 5 per cent to about70 per cent, more preferably from about 10 per cent to about 30 percent.

Methods of preparing these compositions include the step of bringinginto association a compound described herein(s) with the carrier and,optionally, one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation a compound described herein with liquid carriers, or finelydivided solid carriers, or both, and then, if necessary, shaping theproduct.

Compositions of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound describedherein(s) as an active ingredient. A compound may also be administeredas a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules and the like), theactive ingredient is mixed with one or more pharmaceutically-acceptablecarriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: (1) fillers or extenders, such as starches, lactose,sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as,for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol;(4) disintegrating agents, such as agar-agar, calcium carbonate, potatoor tapioca starch, alginic acid, certain silicates, and sodiumcarbonate; (5) solution retarding agents, such as paraffin; (6)absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, acetyl alcohol and glycerolmonostearate; (8) absorbents, such as kaolin and bentonite clay; (9)lubricants, such a talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and(10) coloring agents. In the case of capsules, tablets and pills, thepharmaceutical compositions may also comprise buffering agents. Solidcompositions of a similar type may also be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugars, as well as high molecular weight polyethylene glycols andthe like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved in sterile water, or some other sterile injectable mediumimmediately before use. These compositions may also optionally containopacifying agents and may be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of a compound describedherein include pharmaceutically-acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

In addition to inert diluents, the oral compositions can includeadjuvants such as wetting agents, emulsifying and suspending agents,sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to a compound described herein may containsuspending agents as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,and mixtures thereof.

Pharmaceutical compositions of the invention for rectal or vaginaladministration may be presented as a suppository, which may be preparedby mixing one or more compounds described herein with one or moresuitable nonirritating excipients or carriers comprising, for example,cocoa butter, polyethylene glycol, a suppository wax or a salicylate,and which is solid at room temperature, but liquid at body temperatureand, therefore, will melt in the rectum or vaginal cavity and releasethe active agent.

Compositions of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compounddescribed herein include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. A compound describedherein may be mixed under sterile conditions with apharmaceutically-acceptable carrier, and with any preservatives,buffers, or propellants which may be required.

The ointments, pastes, creams and gels may contain, in addition to acompound described herein, excipients, such as animal and vegetablefats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound describedherein, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

A compound described herein can be alternatively administered byaerosol. This is accomplished by preparing an aqueous aerosol, liposomalpreparation or solid particles containing the compound. A nonaqueous(e.g., fluorocarbon propellant) suspension could be used. Sonicnebulizers are preferred because they minimize exposing the agent toshear, which can result in degradation of the compound.

Ordinarily, an aqueous aerosol is made by formulating an aqueoussolution or suspension of the agent together with conventionalpharmaceutically-acceptable carriers and stabilizers. The carriers andstabilizers vary with the requirements of the particular compound, buttypically include nonionic surfactants (Tweens, Pluronics, orpolyethylene glycol), innocuous proteins like serum albumin, sorbitanesters, oleic acid, lecithin, amino acids such as glycine, buffers,salts, sugars or sugar alcohols. Aerosols generally are prepared fromisotonic solutions.

Transdermal patches have the added advantage of providing controlleddelivery of a compound described herein to the body. Such dosage formscan be made by dissolving or dispersing the agent in the proper medium.Absorption enhancers can also be used to increase the flux of the activeingredient across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the activeingredient in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of the invention.

Pharmaceutical compositions of the invention suitable for parenteraladministration comprise one or more compounds described herein incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containantioxidants, buffers, bacteriostats, solutes which render theformulation isotonic with the blood of the intended recipient orsuspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers, which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents which delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofone or more compounds described herein in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue.

When a compound described herein is administered as a pharmaceutical, tohumans and animals, they can be given per se or as a pharmaceuticalcomposition containing, for example, 0.1 to 99.5% (more preferably, 0.5to 90%) of active ingredient in combination with apharmaceutically-acceptable carrier.

Regardless of the route of administration selected, a compound describedherein, which may be used in a suitable hydrated form, and/or thepharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels and time course of administration of the activeingredients in the pharmaceutical compositions of the invention may bevaried so as to obtain an amount of the active ingredient which iseffective to achieve the desired therapeutic response for a particularpatient, composition, and mode of administration, without being toxic tothe patient. An exemplary dose range is from 0.1 to 10 mg per day.

A preferred dose of a compound described herein is the maximum that apatient can tolerate and not develop serious side effects. Preferably,the compound of the present invention is administered at a concentrationor amount of about 0.001 mg to about 100 mg per kilogram of body weight,about 0.01-about 50 mg/kg or about 10 mg-about 30 mg/kg of body weight.Ranges intermediate to the above-recited values are also intended to bepart of the invention.

The invention is further illustrated by the following examples which areintended to illustrate but not limit the scope of the invention.

EXAMPLES Chemical Synthesis

General.

All exemplified target compounds are fully analyzed and characterized(mp, TLC, LCMS, ¹H-NMR) prior to submission for biological evaluation.Thin-layer chromatography was carried out on Merck Si 250F plates.Visualization was accomplished with ultraviolet exposure or withphosphomolybdic acid. Flash chromatography and Isco (CombiFlash) wascarried out on silica gel (60 M). MS were carried out on a Agilent 1100and 1200 series HPLC-Mass Spectrometer. ¹H and ¹³C NMR spectra wererecorded at 300 and 75 MHz, respectively, on a Jeol Eclipse 300Spectrometer or ¹H NMR spectra were recorded at 400 MHz on a Avance III400 Ultra shield-plus TM digital Spectrometer or 300 MHz Varian. NMRassignments are based on a combination of the ¹H, ¹³C, ¹H COSY, HMBC andHMQC spectra. Coupling constants are given in hertz (Hz). Anhydrousmethylene chloride, tetrahydrofuran, and dimethylformamide are AldrichSure/Seal™, and other materials are reagent grade.

Example 12-(4-(4-chlorobenzyloxy)-1-ethyl-6-fluoro-1H-indol-3-yl)-N,N-dimethylethanamine(1-10b) Synthesis of2-(4-Benzyloxy-5-fluoro-1H-indol-3-yl)-N,N-dimethylethanamine (1-7a)Step 1 and 2: Methyl 4-benzyloxy-5-fluoro-1H-indole-2-carboxylate (1-3a)

In a pre-dried 3-neck roundbottom flask was added anhydrous MeOH (100mL), followed by Na metal (5.52 g, 0.24 mol) portionwisely at 0° C. Theresulting solution was cooled in a dry ice/acetone bath to −20° C. Asolution of 1-1a (prepared according to U.S. Pat. No. 5,330,992 or fromcommercial sources) (18.4 g, 0.08 mol) and methyl azidoacetate (27.6 g,0.24 mol) in dry MeOH (50 mL) was added dropwise over 60 min. Afterstirring for 1 h, the reaction was warmed to room temperature andstirring continued for 1.5 h. The heterogeneous mixture was then pouredonto ice, and the precipitate was collected by filtration. The yellowsolid (1-2a) was immediately dissolved in p-xylenes (400 mL) and thesolution was washed with brine, followed by drying over Na₂SO₄. Afterfiltration the resulting solution was heated at reflux until TLCindicated the reaction was complete (about 1 h). The solvent wasdistilled under reduced pressure to precipitate the product as whitecrystals (6.73 g). An additional 1.36 g of product (1-3a) was obtainedby chromatography of the residue on silica gel, eluting withEtOAc/hexanes (overall yield 35%). ¹H NMR (300 MHz, CDCl₃-d) δ (ppm)3.94 (s, 3H), 5.33 (s, 2H), 6.98-7.03 (m, 1H), 7.10 (dd, 1H, J=11.8,8.8), 7.29-7.41 (m, 4H), 7.48-7.50 (m, 2H), 8.81 (br, 1H). APCI [M+1]:300.2.

Step 3: 4-(Benzyloxy)-5-fluoro-1H-indole-2-carboxylic acid (1-4a)

Compound 1-3a was added to a solution of aqueous 2 N NaOH. Thesuspension was stirred at 80-90° C. until the reaction mixture becameclear and was then held at reflux for 1-2 h. The solution was cooled andacidified with aqueous 3 N HCl, then the resulting precipitate wascollected by filtration, washed with water, and dried under vacuum overP₂O₅ to provide the product (1-4a) in 99% yield. ¹H NMR (CDCl₃-d, 300MHz) δ (ppm) 5.31 (s, 2H), 7.06-7.18 (m, 3H), 7.30-7.42 (m, 3H),7.47-7.50 (m, 2H), 11.93 (bs, 1H).

Step 4: 4-Benzyloxy-5-fluoro-1H-indole (1-5a)

Compound 1-4a (6.28 g, 0.022 mol), copper powder (7.05 g, 0.11 mol) and2-phenylpyridine (50 mL) were heated at reflux (230-240° C.) under astream of nitrogen for 10 min, by which time TLC analysis showedcomplete reaction. The reaction mixture was cooled, filtered throughCelite, and the filter cake was washed with EtOAc. The filtrate andEtOAc washings were combined, diluted with water, and extracted threetimes with EtOAc. The organic extract was washed with 1 N HCl, H₂O andbrine, dried with NaSO₄, and concentrated. The resulting residue waspurified by column chromatography on silica gel eluting withEtOAc/hexanes to give the product as a greenish solid (1-5a) in 62%yield, 3.32 g. ¹H NMR (300 MHz, CDCl₃-d) δ (ppm) 5.31 (s, 2H), 6.62-6.64(m, 1H), 6.93-7.03 (m, 2H), 7.15 (dd, 1H, J=3.0, 2.5), 7.31-7.40 (m,3H), 7.49-7.52 (m, 2H), 8.12 (br, 1H). APCI [M+1]: 242.1.

Step 5:2-(4-Benzyloxy-5-fluoro-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide(1-6a)

A solution of oxalyl chloride (0.78 mL, 8.963 mmol) in anhydrous ether(20 mL) was added dropwise over 20 min to a 0° C. solution of 1-5a (1.44g, 5.975 mmol) in anhydrous ether (20 mL). The reaction mixture wasstirred at room temperature for 5 h, cooled to −20° C., and treated witha stream of dimethyl amine gas. The reaction was diluted with EtOAc,washed with water and brine, and dried over Na₂SO₄. After concentration,the resulting residue was recrystallized from EtOAc to provide theproduct (1-6a) as white crystals in 87% yield, 1.58 g. ¹H NMR (300 MHz,CDCl₃-d) δ (ppm) 2.92 (s, 3H), 2.94 (s, 3H), 5.17 (s, 2H), 6.91-7.00 (m,2H), 7.29-7.37 (m, 3H), 7.58-7.61 (m, 2H), 7.70-7.72 (m, 1H), 10.02 (br,1H). APCI [M+1]: 341.2.

Step 6: 2-(4-Benzyloxy-5-fluoro-1H-indol-3-yl)-N,N-dimethylethanamine(1-7a)

A solution of 1-6a (2.26 g, 6.647 mmol) in dry 1,4-dioxane (30 mL) wasadded dropwise to a slurry of LiAlH₄ (2.52 g, 66.47 mmol) in dry1,4-dioxane (40 mL) at reflux. The mixture was held at reflux for 1 h.The mixture was then cooled, quenched with ice-water (mixed with NaOH),filtered through Celite, and the filter cake was washed with EtOAc. Thefiltrate and EtOAc washings were combined and extracted three times withEtOAc. The organic layer was washed with 1 N NaOH and brine, dried overNa₂SO₄ and concentrated. The resulting residue was purified by columnchromatography on silica gel with CH₂Cl₂ (100%) to 5% NH₄OH in CH₂Cl₂ aseluent to give the product (1-7a) as a brown oil in 80% yield, 1.67 g.¹H NMR (300 MHz, CDCl₃-d) δ (ppm) 2.14 (s, 6H). 2.52-2.57 (m, 2H),2.91-2.97 (m, 2H), 5.25 (s, 2H), 6.92-6.98 (m, 3H), 7.31-7.40 (m, 3H),7.49-7.52 (m, 2H), 7.97 (br, 1H). APCI [M+1]: 313.1.

Synthesis of 3-(2-Dimethylaminoethyl)-7-fluoro-1-methyl-1H-indol-4-ol(1-9c) Step 1 to 6:2-(4-Benzyloxy-7-fluoro-1H-indol-3-yl)-N,N-dimethylethanamine (1-7c)

Following the procedures (step 1-6) used to prepare compound 1-7a,compound 1-1c was used as starting material to obtain compound 1-7c.

Step 7: 4-Benzyloxy-3-(2-dimethylaminoethyl)-7-fluoro-1-methyl-1H-indole(1-8c)

At 0° C., NaH (2 eq) was added to a solution of 1 eq of compound 1-7c inDMF. After 30 min, a solution of 0.1 M methyl iodide in DMF was addedslowly over 30 min, and then the reaction mixture was allowed to warm to25° C. and stirred at that temperature for 1 h. After standard workup,the brown oil residue was purified by column chromatography, elutingwith CH₂Cl₂/2% NH₄OH. A brown oil (1-8c) was obtained in 84% yield. ¹HNMR (CDCl₃-d, 300 MHz) δ (ppm) 2.13 (s, 6H), 2.50-2.56 (m, 2H),2.95-3.01 (m, 2H), 3.89 (d, 3H, J=1.9), 5.13 (s, 2H), 6.29 (dd, 1H,J=8.5, 2.8), 6.67 (dd, 1H, J=8.5, 12.1), 6.69 (s, 1H), 7.29-7.40 (m,3H), 7.45-7.48 (m, 2H). APCI [M+1]: 327.2.

Step 8: 3-(2-Dimethylaminoethyl)-7-fluoro-1-methyl-1H-indol-4-ol (1-9c)

A mixture of 1-8c and Pd(OH)₂/C in MeOH was hydrogenated at ambientpressure for 2 h at 25° C., then the mixture was filtered through a plugof Celite and washed with EtOAc. The crude product was purified bycolumn chromatography eluting with CH₂Cl₂/2% NH₄OH to give a white solid(1-9c) in 88% yield. ¹H NMR (CDCl₃-d, 300 MHz)

ppm 2.35 (s, 6H), 2.63-2.67 (m, 2H), 2.86-2.89 (m, 2H), 3.87 (d, 3H,J=2.2), 6.33 (dd, 1H, J=8.2, 3.3), 6.61 (s, 1H), 6.69 (dd, 1H, J=8.5,12.4). APCI [M+1]: 237.2.

Synthesis of2-(4-(4-chlorobenzyloxy)-1-ethyl-6-fluoro-1H-indol-3-yl)-N,N-dimethylethanamine(1-10b, Example 1) Step 1 to 6:2-(4-Benzyloxy-6-fluoro-1H-indol-3-yl)-N,N-dimethylethanamine (1-7b)

Following the procedures (step 1-6, scheme 1) used to prepare compound1-7a, compound 1-1b was used as starting material to obtain compound1-7b.

Step 7-8: 3-(2-(dimethylamino)ethyl)-1-ethyl-6-fluoro-1H-indol-4-ol(1-9b)

Following the procedures (step 7-8 scheme 1) used to prepare compound1-9c, compound 1-7b was used as starting material to obtain compound1-9b.

Step 9:2-(4-(4-chlorobenzyloxy)-1-ethyl-6-fluoro-1H-indol-3-yl)-N,N-dimethylethanamine(1-10b)

Following the procedure (step 7, scheme 1) used to prepare compound1-8c, compound 1-9b and 1-chloro-4-(chloromethyl)benzene were used asstarting material to obtain compound 1-10b.

1H NMR (CDCl₃-d) δ (ppm): 12.14 (br.s, 1H), 7.41-7.46 (m, 4H), 6.92 (s,1H), 6.65 (dd, J1=2.0 Hz, J2=7.8 Hz, 1H), 6.38 (dd, J1=2.0 Hz, J2=5.2Hz, 1H), 5.06 (s, 2H), 4.00 (q, J=7.2 Hz, 2H), 3.22-3.26 (m, 2H),3.06-3.10 (m, 2H), 2.41 (s, 6H), 1.39 (t, J=3.2 Hz, 3H).

The compounds in table I were made according to processes described inscheme 1.

TABLE I Ex. ID Procedure of Strucutre name number number NMR MS scheme

2-(4-(4- chlorobenzyl- oxy)-1-ethyl- 6-fluoro-1H- indol-3-yl)- N,N-dimethylethan- amine 1 1-10b 1H NMR (CDCl₃-d) δ (ppm) 12.14 (br.s, 1H),7.41- 7.46 (m, 4H), 6.92 (s, 1H), 6.65 (dd, J1 = 2.0 Hz, J2 = 7.8 Hz,1H), 6.38 (dd, J1 = 2.0 Hz, J2 = 5.2 Hz, 1H), 5.06 (s, 2H), 4.00 (q, J =7.2 Hz, 2H), 3.22-3.26 (m, 2H), 3.06-3.10 (m, 2H), 2.41 (s, 6H), 1.39(t, J = 3.2 Hz, 3H) calc 374.1, found 375.1 [MH]+ 1

2-(1-ethyl-6- fluoro-4-(4- (trifluoromethoxy)- benzyloxy)-1H-indol-3-yl)- N,N- dimethylethan- amine 2 1-11b 1H NMR (CDCl₃-d) δ(ppm) 11.97 (br.s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.0 Hz,2H), 6.95 (s, 1H), 6.66 (dd, J1 = 2.0 Hz, J2 = 7.8 Hz, 1H), 6.40 (dd, J1= 2.0 Hz, J2 = 9.8 Hz, 1H), 5.10 (s, 2H), 4.01 (q, J = 7.2 Hz, 2H),3.22- 3.26 (m, 2H), 3.08-3.12 (m, 2H), 2.39 (d, J = 4.4 Hz, 6H), 1.40(t, J = 7.2 Hz, 3H) calc 424.2 found 425.1 [MH]+ 1

2-(1-ethyl-6- fluoro-4-(4- (trifluoromethyl)- benzyloxy)- 1H-indol-3-yl)-N,N- dimethylethan- amine 3 1-12b 1H NMR (CDCl₃-d) δ (ppm) 12.28(br.s, 1H), 7.72 (s, 2H), 7.65 (s, 2H), 6.98 (br.s, 1H), 6.66 (d, J =9.6 Hz, 1H), 6.38 (d, J = 9.2 Hz, 1H), 5.19 (s, 2H), 4.02 (s, 2H), 3.30(s, 2H), 3.12 (s, 2H), 2.44 (br.s, 6H), 1.41 (s, 3H) calc 408.2, found409.1 [MH]+ 1

2-(1-ethyl-6- fluoro-4-(2- (trifluoromethyl)- benzyloxy)- 1H-indol-3-yl)-N,N- dimethylethan- amine 4 1-13b 1H NMR (CDCl₃-d) δ (ppm) 7.77(d, J = 8.0 Hz, 1H), 7.64-7.71 (m, 2H), 7.53 (t, J = 7.2 Hz, 1H), 6.92(s, 1H), 6.66 (dd, J1 = 1.6 Hz, J2 = 2.3 Hz, 1H), 6.39 (dd, J1 = 1.6 Hz,J2 = 9.7 Hz, 1H), 5.28 (s, 2H), 4.01 (q, J = 7.2 Hz, 2H), 3.19-3.23 (m,2H), 3.01-3.05 (m, 2H), 2.34 (s, 6H), 1.40 (t, J = 7.2 Hz, 3H) calc408.2, found 409.1 [MH]+ 1

2-(1-ethyl-6- fluoro-4-(4- fluorobenzyl- oxy)-1H- indol-3-yl)- N,N-dimethylethan- amine 5 1-14b 1H NMR (CDCl₃-d) ppm: 11.93 (br.s, 1H),7.51 (s, 2H), 7.17 (t, J = 7.6 Hz, 2H), 6.97 (s, 1H), 6.68 (d, J = 9.2Hz, 1H), 6.43 (d, J = 9.6 Hz, 1H), 5.08 (s, 2H), 4.03 (d, J = 6.4 Hz,2H), 3.26 (s, 2H), 3.12 (s, 2H), 2.43 (s, 6H), 1.42 (t, J = 6.4Hz, 3H)calc 358.2, found 359.1 [MH]+ 1

2-(1-ethyl-6- fluoro-4-(4- methoxybenzyl- oxy)-1H- indol-3-yl)-N,N-dimethyl- ethanamine 6 1-15b 1H NMR (CDCl₃-d) δ (ppm) 7.41 (d, J =8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.87 (s, 1H), 6.63 (dd, J1 = 2.4Hz, J2 = 7.6 Hz, 1H), 6.41 (dd, J1 = 2.0 Hz, J2 = 9.7 Hz, 1H), 5.01 (s,2H), 4.00 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 3.13- 3.17 (m, 2H), 2.95-2.99 (m, 2H), 2.27 (s, 6H), 1.40 (t, J = 7.6 Hz, 3H) calc 370.2, found371.1 [MH]+ 1

2-(1-ethyl-6- fluoro-4-(3- (trifluoromethyl)- benzyloxy)- 1H-indol-3-yl)-N,N- dimethylethan- amine 7 1-16b 1H NMR (CDCl₃-d) δ (ppm) 7.76(s, 1H), 7.58- 7.72 (m, 3H), 6.92 (s, 1H), 6.66 (dd, J1 = 2.4 Hz, J2 =7.6 Hz, 1H), 6.39 (dd, J1 = 2.0 Hz, J2 = 9.1 Hz, 1H), 5.17 (s, 2H), 4.01(q, J = 7.2 Hz, 2H), 3.18-3.23 (m, 2H), 2.961-3.00 (m, 2H), 2.33 (s,6H), 1.41 (t, J = 7.2 Hz, 3H) calc 408.2, found 409.1 [MH]+ 1

2-(1-ethyl-6- fluoro-4-(5- fluoro-2- methylbenzyloxy)- 1H- indol-3-yl)-N,N- dimethylethan- amine 8 1-17b 1H NMR (CDCl₃-d) δ (ppm) 7.17-7.21 (m,2H), 6.95-7.00 (m, 1H), 6.84 (s, 1H), 6.64 (dd, J1 = 2.0 Hz, J2 = 7.8Hz, 1H), 6.37 (dd, J1 = 2.0 Hz, J2 = 9.8 Hz, 1H), 5.07 (s, 2H), 4.01 (t,J = 7.2 Hz, 2H), 3.04-3.08 (m, 2H), 2.72-2.77 (m, 2H), 2.37 (d, J = 7.6Hz, 3H), 2.20 (s, 6H), 1.41 (t, J = 7.6 Hz, 3H) calc 372.2, found 373.1[MH]+ 1

2-(1-ethyl-6- fluoro-4- (pyridin-4- ylmethoxy)- 1H-indol-3- yl)-N,N-dimethylethan- amine 9 1-18b ¹H NMR (CDCl₃) δ (ppm) 8.63 (dd, J = 4.5,1.5 Hz, 2H), 7.42 (d, J = 5.9 Hz, 2H), 6.81 (s, 1H), 6.62 (dd, J = 9.6,1.9 Hz, 1H), 6.25 (dd, J = 11.5, 1.9 Hz, 1H), 5.19 (s, 2H), 4.01 (q, J =7.3 Hz, 2H), 3.10-3.01 (m, 2H), 2.65-2.55 (m, 2H), 2.22 (s, 6H), 1.41(t, J = 7.3 Hz, 3H), Calc 341.2, found [MH]+ 342.4 1

2-(1-ethyl-6- fluoro-4- (thiophen-3- ylmethoxy)- 1H-indol-3- yl)-N,N-dimethylethan- amine 10 1-19b ¹H-NMR (400 MHz, CDCl₃): δ (ppm) 7.39 (d,J = 2.0 Hz, 1H), 7.35-7.33 (m, 1H), 7.19 (d, J = 5.2 Hz, 1H), 6.77 (s,1H), 6.59 (dd, J = 8.0, 1.6 Hz, 1H), 6.34 (dd, J = 10.0, 1.6 Hz, 1H),5.14 (s, 2H), 4.01 (q, 2H), 2.98 (t, J = 7.6 Hz, 2H), 2.59-2.55 (m, 2H),2.17 (s, 6H), 1.39 (t, J = 7.2 Hz, 3H). calc 346.2, found 347.1 [MH]+ 1

2-(5-fluoro- 1-methyl-4- (thiophen-2- ylmethoxy)- 1H-indol-3- yl)-N,N-dimethylethan- amine 11 1-20a 1H NMR (300 MHz, MeOD-d6) δ (ppm) 7.44-7.35 (m, 1H), 7.12 (d, J = 2.9 Hz, 1H), 7.04-6.89 (m, 4H), 5.41 (s, 2H),3.69 (s, 3H), 2.98-2.87 (m, 2H), 2.69-2.58 (m, 2H), 2.24 (s, 6H) calc332.14, found 333.1 [MH]+ 1

Example 112-(1-ethyl-7-fluoro-4-(2-nitrophenoxy)-1H-indol-3-yl)-N,N-dimethylethanamine(2-2)

Following the procedure (step 7, scheme 1) used to prepare compound1-8c, compound 2-1 (prepared according to step 1-8, scheme 1) in DMSOand 1-fluoro-2-nitrobenzene were used as starting material to obtaincompound 2-2.

Example 122-(3-(2-(dimethylamino)ethyl)-1-ethyl-7-fluoro-1H-indol-4-yloxy)aniline(2-3)

Following the procedure (step 8, scheme 1) used to prepare compound1-9c, compound 2-2 was used as starting material, using Pd/C (10%) assource of Pd to obtain compound 2-3.

The compounds in table 2 were made according to processes described inscheme 2.

TABLE 2 Ex. ID Procedure Strucutre name number number NMR MS of scheme

2-(1-ethyl-7- fluoro-4-(2- nitrophenoxy)- 1H-indol-3- yl)-N,N-dimethylethanamine 11 2-2 1H NMR (CDCl₃-d) δ (ppm): 8.07 (dd, J1 = 1.6Hz, J2 = 6.3Hz, 1H), 7.59- 7.64 (m, 2H), 7.29 (dd, J1 = 2.0 Hz, J2 = 7.8Hz, 1H), 6.90-6.95 (m, 2H), 6.54 (dd, J1 = 3.2 Hz, J2 = 6.1 Hz, 1H),4.28 (q, J = 7.2 Hz, 2H), 2.68 (t, J = 7.2 Hz, 2H), 2.37 (t, J = 7.2 Hz,2H), 2.03 (d, J = 7.6 Hz, 6H), 1.37 (t, J = 4.8 Hz, 3H) calc 371.2 found372.0[MH]+ 2

2-(3-(2- (dimethylamino)- ethyl)-1-ethyl-7- fluoro-1H- indol-4-yloxy)aniline 12 2-3 1H NMR (CDCl₃-d) δ (ppm) 6.92-6.96 (m, 1H), 6.87(s, 1H), 6.82 (dd, J1 = 1.2 Hz, J2 = 6.5 Hz, 1H), 6.78 (dd, J1 = 1.6 Hz,J2 = 6.6 Hz, 1H), 6.65- 6.72 (m, 2H), 6.29 (dd, J1 = 3.2 Hz, J2 = 6.1Hz, 1H), 4.41 (br.s, 2H), 4.27 (q, J = 7.6 Hz, 2H), 3.02 (t, J = 7.6 Hz,2H), 2.70 (dd, J1 = 3.6 Hz, J2 = 4.1 Hz, 2H), 2.30 (s, 6H), 1.45 (t, J =7.2 Hz, 3H) Calc 341.2, found 342.0[MH]+ 2

Example 142-(6-(benzyloxy)-5-fluoro-1H-indol-3-yl)-N,N-dimethylethanamine (4-5)Step 1: 6-Benzyloxy-5-fluoro-1H-indole-2-carboxylic acid (4-2)

A suspension of compound 4-1, prepared according to WO2005/123716, (3.09g, 10.3 mmol) in 150 mL of 2 M NaOH solution was heated at reflux for 4h. The clear solution was cooled to 0° C., and acidified by 3 M HCl topH-1, as white precipitate appeared. The suspension was filtered andwashed with water, and then dried under vacuum (75° C.) overnight.Compound 4-2 was obtained as a white solid (2.89 g, 98%). ¹H NMR(DMSO-d₆, 300 MHz) 5.19 (s, 2H), 7.01 (d, 1H, J=1.6), 7.09 (d, 1H,J=8.0), 7.32-7.52 (m, 6H), 11.70 (bs, 1H). APCI [M−1]: 284.

Step 2: 6-Benzyloxy-5-fluoro-1H-indole (4-3)

A mixture of compound 4-2 (2.58 g, 9.07 mmol) and copper (2.97 g, 45.1mmol) in 80 mL of 1-methylpyrrolidin-2-one was heated at refluxovernight under nitrogen. After cooling to room temperature, the mixturewas filtered through Celite and washed with EtOAc. The filtrate waspartitioned between water and EtOAc (2×150 mL). The combined organicphase was washed with water and brine, and then dried over anhydrousNa₂SO₄. The black residue was purified by column chromatography(hexanes/EtOAc 2% to 12%) to give compound 4-3 (1.31 g, 60%) as a whitesolid. ¹H NMR (CDCl₃, 300 MHz) 5.16 (s, 2H), 6.94-6.98 (m, 1H), 6.96 (d,1H, J=7.1), 7.10-7.14 (m, 1H), 7.29-7.42 (m, 4H), 7.44-7.50 (m, 2H),8.01 (bs, 1H). APCI [M−1]: 240.

Step 3:2-(6-Benzyloxy-5-fluoro-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (4-4)

Following the procedure used to prepare compound 1-6a (step 5, scheme1), compound 4-3 gave compound 4-4 in 82% yield as a white solid. ¹H NMR(CDCl₃, 300 MHz) 3.06 (s, 3H), 3.08 (s, 3H), 5.14 (s, 2H), 6.94 (d, 1H,J=6.9), 7.32-7.47 (m, 5H), 7.82 (d, 1H, J=3.0), 8.05 (d, 1H, J=11.3),8.96 (bs, 1H). APCI [M+1]: 386.2.

Step 4: 2-(6-Benzyloxy-5-fluoro-1H-indol-3-yl)-N,N-dimethylethanamine(4-5)

Following the procedure used to prepare compound 1-7a (step 6 scheme 1),compound 4-4 gave compound 4-5 in 77% yield as a brown oil.

The compound in table 4 was made according to processes described inscheme 4.

TABLE 4 Ex. ID Procedure Strucutre name number number NMR MS of scheme

2-(6- (benzyloxy)- 5-fluoro-1H- indol-3-yl)- N,N- dimethylethan- amine14 4-5 ¹H NMR (DMSO-d₆) (HCl salt) δ (ppm) 10.89 (s, 1H), 7.33-7.50 (m,7H), 7.17 (m, 1H), 7.10 (d, J = 7.4 Hz, 1H), 3.24-3.30 (m, 2H),2.99-3.07 (m, 2H), 2.82 (s, 6H). calc 312.2, found 313.1 [MH]⁺ 4

Example 162-(4-methoxy-1-methyl-7-phenyl-1H-indol-3-yl)-N,N-dimethylethanamine(6-6) Step 1:2-(7-Bromo-4-hydroxy-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (6-2)

To a solution of compound 6-1, prepared according to Helv. Chim. Acta,1959, 42, 1557 (3.22 g, 10 mmol) in CH₂Cl₂ (90 mL) and ether (75 mL) wasadded pyridinium hydrobromide perbromide and the reaction mixture wasstirred overnight at 25° C. Solvent was removed under reduced pressureand the crude material was purified by column chromatography (elutionwith ethyl acetate/hexanes) to give compound 6-2 (2.04 g, 65%) as ayellow solid. ¹H NMR (CD₃OD, 300 MHz) δ (ppm) 3.07 (s, 3H), 3.11 (s,3H), 6.57 (d, 1H, J=8.5), 7.30 (d, 1H, J=8.5), 7.98 (s, 1H). APCI [M+1]:311, 3.

Step 2:2-(7-Bromo-4-methoxy-1-methyl-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide(6-3)

To a solution of compound 6-2 (1.28 g, 4.12 mmol) in DMF at 0° C. wasadded NaH (660 mg, 16.5 mmol) and the reaction mixture was stirred for10 min. To this reaction mixture, methyl iodide (3.5 g, 24.7 mmol) wasadded slowly and the reaction was monitored by MS. After 2 h, thereaction was quenched by adding water and EtOAc and washed with water,dried, and concentrated. The crude product was purified by columnchromatography (1% NH₄OH/1% MeOH/EtOAc) to obtain compound 6-3 (1.30 g,92%) as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 3.07 (s, 3H),3.09 (s, 3H), 3.88 (s, 3H), 4.19 (s, 3H), 6.51 (d, 1H, J=8.5), 7.32 (d,1H, J=8.5), 7.79 (s, 1H). APCI [M+1]: 339, 341.

Step 3:1-(7-Bromo-4-methoxy-1-methyl-1H-indol-3-yl)-2-(dimethylamino)ethanol(6-4)

To a slurry of LiAlH₄ (419 mg, 11.03 mmol) in anhydrous THF at 0° C.under a nitrogen atmosphere was added AlCl₃ (488 mg, 3.67 mmol) and thereaction mixture was stirred for 10 min. To this slurry was then addedcompound 6-3 (500 mg, 1.47 mmol) and stirring continued for 30 min bywhich time MS showed no starting material. The reaction was quenched byadding water, extracted by ether, dried, and concentrated. The crudematerial was purified by column chromatography to give compound 6-4 (480mg, 90%) as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 2.42 (s, 6H),2.58 (dd, 1H, J=12.4, 9.6), 2.71 (dd, 1H, J=12.4, 3.3), 3.89 (s, 3H),4.08 (s, 3H), 5.28 (dd, 1H, J=9.2, 3.0), 6.33 (d, 1H, J=8.5), 6.97 (s,1H), 7.20 (d, 1H, J=8.3). APCI [M+1]: 309, 311, 327, 329.

Step 4:2-(7-Bromo-4-methoxy-1-methyl-1H-indol-3-yl)-N,N-dimethylethanamine(Compound 6-5)

To a solution of compound 6-4 (430 mg, 1.31 mmol) in anhydrous CH₂Cl₂(20 mL) at 0° C. was added Et₃SiH (1.52 g, 13.1 mmol) and the reactionmixture was stirred for 10 min. To this mixture was added CF₃CO₂H (1.2g, 10.5 mmol) and stirring continued for 30 min. The reaction wasquenched by adding sodium bicarbonate and it was extracted with CH₂Cl₂and washed by water and brine. The organic layer was dried over sodiumsulfate and concentrated. The crude material was purified by columnchromatography (2% NH₄OH in CH₂Cl₂) to get compound 6-5 (76 mg, 12%) asan off-white solid. ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 2.31 (s, 6H),2.51-2.57 (m, 2H), 2.95-3.02 (m, 2H), 3.87 (s, 3H), 4.06 (s, 3H), 6.30(d, 1H, J=8.3), 6.67 (s, 1H), 7.17 (d, 1H, J=8.5). APCI [M+1]: 311.2,313.2.

General Procedure for Preparation of 6-6, 6-7, 6-8, 6-9, 6-10, 6-13 and6-14:

To a clean dry sealed tube containing palladium catalyst (4% mol) of(tetrakis-(triphenylphosphine) palladium (0) ordichlorobis(triphenylphosphine) palladium (II)) was added arylboronicacid (1.1 eq) (or pinacol boronate esters) and potassium(sodium)carbonate (2 eq). The tube was sealed and the air displaced withnitrogen before the addition of dry degassed 1,4-dioxane (5 mL) followedby compound 6-5 (1.0 eq). The mixture was heated at 150° C. either in amicrowave for 10 to 30 min or in an oil bath for 16 h. The reaction wascooled to room temperature, filtered, evaporated to dryness and purifiedby column chromatography using CH₂Cl₂/NH₄OH (2-5%) as the eluent. Theproducts were further purified by reverse phase chromatography (C-18)using gradient MeOH/H₂O (0.1% TFA) as the eluent. Appropriate fractionswere combined, neutralized, evaporated to dryness and the products wereidentified by ¹H NMR, MS and HPLC.

Step 5:2-(4-Methoxy-1-methyl-7-phenyl-H-indol-3-yl)-N,N-dimethylethanaminehydrochloride (6-6)

Prepared using phenylboronic acid, potassium carbonate andtetrakis-(triphenylphosphine) palladium (0) in an oil bath heating for16 h and the compound was converted to hydrochloride salt. Obtained alight blue solid, mp 285-287° C.

Example 172-[4-Methoxy-1-methyl-7-(thiophen-2-yl)-1H-indol-3-yl]-N,N-dimethylethanamine(6-7)

Prepared using thiophen-2-ylboronic acid, sodium carbonate anddichloro-bis(triphenylphosphine) palladium (II) in a microwave heatingfor 30 min. Obtained off-white solid, mp 131-133° C.

Example 182-[7-(Furan-2-yl)-4-methoxy-1-methyl-1H-indol-3-y]-N,N-dimethylethanamine(6-8)

Prepared using furan-2-ylboronic acid, sodium carbonate anddichloro-bis(triphenylphosphine) palladium (II) in a microwave heatingfor 10 min. Obtained off-white solid, mp 90-93° C.

Example 192-[7-(Furan-3-yl)-4-methoxy-1-methyl-1H-indol-3-y]-N,N-dimethylethanamine(6-9)

Prepared using pinacol furan-3-ylboronate ester, sodium carbonate anddichloro-bis(triphenylphosphine) palladium (II) in a microwave heatingfor 30 min. Obtained white solid, mp 80-81° C.

Example 202-[4-Methoxy-1-methyl-7-(1H-pyrrol-2-yl)-1H-indol-3-yl]-N,N-dimethylethanamine(6-10)

Prepared using N-Boc-pyrrol-2-ylboronic acid, sodium carbonate anddichloro-bis(triphenylphosphine) palladium (II) in a microwave heatingfor 30 min. The Boc group was cleaved by TFA during reverse phasechromatography. Obtained a gray solid, mp 203-206° C.

Example 232-[4-Methoxy-1-methyl-7-(thiophen-3-yl)-1H-indol-3-yl]-N,N-dimethylethanamine(6-13)

Prepared according to the general coupling method in usingthiophen-3-ylboronic acid, sodium carbonate anddichlorobis(triphenylphosphine) palladium (II) in a microwave heatingfor 60 min. Obtained brown solid, mp 120-122° C.

Example 242-(4-Methoxy-1-methyl-7-(pyridin-3-yl)-1H-indol-3-yl)-N,N-dimethylethanamine(6-14)

Prepared according to the general coupling method in using pinacolpyridine-3-ylboronate ester, potassium carbonate, copper(I) iodide andtetrakis-(triphenylphosphine) palladium (0) in an oil bath heating for 4h. Obtained a yellow solid, mp 227-230° C.

Example 213-[3-(2-Dimethylaminoethyl)-4-methoxy-1-methyl-1H-indol-7-yl]prop-2-yn-1-ol(6-11)

In a clean dry sealed tube, copper iodide (4 mg, 10% mol) was added to amixture of dichlorobis(triphenylphosphine) palladium (II) (17 mg, 10%mol), compound 6-5 (62 mg, 0.2 mmol) and propargyl alcohol (35 L, 0.6mmol) in dry triethylamine (3 mL) under nitrogen. The mixture was heatedat 150 OC in a microwave for 2 h. The reaction was cooled to roomtemperature, filtered, evaporated to dryness and purified by columnchromatography using CH₂Cl₂/NH₄OH as the eluent, giving a brown solid(30 mg, 53%), mp 101-104° C.

Example 223-(2-dimethylaminoethyl)-4-methoxy-1-methyl-N-phenyl-1H-indol-7-amine(6-12)

In a clean dry sealed tube, sodium tert-butylate (20 mg, 0.2 mmol) wasadded to a mixture of tris(dibenzylideneacetone)dipalladium(0) (18 mg,20% mol), 2.2′-bis(dipbenylphosphino)-1.1′-binaphthyl (26 mg, 40%),compound 6-5 (31 mg, 0.1 mmol) and aniline (14 mg, 0.15 mmol) in drytoluene (3 mL) under nitrogen. The mixture was heated at 120° C. in anoil bath for 16 h. The reaction was cooled to room temperature,filtered, evaporated to dryness and purified by column chromatographyusing CH₂Cl₂/NH₄OH as the eluent, giving red solid, mp 158-160° C.

The compounds in table 6 were made according to processes described inscheme 6.

TABLE 6 Ex. ID Procedure Strucutre name number number NMR MS of scheme

2-(4- methoxy-1- methyl-7- phenyl-1H- indol-3-yl)- N,N- dimethylethan-amine 16 6-6 ¹H NMR (DMSO-d₆) (HCl salt) δ (ppm) 10.14 (bs, 1H),7.33-7.46 (m, 5H), 7.04 (s, 1H), 6.83 (d, J = 7.7 Hz, 1H), 6.58 (d, J =8.0 Hz, 1H), 3.92 (s, 3H), 3.22-3.29 (m, 2H), 3.18 (s, 3H), 3.13- 3.19(m, 2H), 2.83 (s, 6H). calc 308.2, found 309.2 [MH]⁺ 6

2-(4- methoxy-1- methyl-7- (thiophen-2- yl)-1H-indol- 3-yl)-N,N-dimethylethan- amine 17 6-7 ¹H NMR (CDCl₃) δ (ppm) 7.32 (dd, J = 1.1,5.0 Hz, 1H), 7.05 (dd, J = 3.3, 5.2 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H),7.00 (dd, J = 1.1, 3.4 Hz, 1H), 6.67 (s, 1H), 6.47 (d, J = 8.0 Hz, 1H),3.93 (s, 3H), 3.33 (s, 3H), 3.02-3.08 (m, 2H), 2.60-2.66 (m, 2H), 2.36(s, 6H). calc 314.2, found 315.2 [MH]⁺ 6

2-(7-(furan- 2-yl)-4- methoxy-1- methyl-1H- indol-3-yl)- N,N-dimethylethan- amine 18 6-8 ¹H NMR (CDCl₃) δ (ppm) 7.51 (s, 1H), 7.06(d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 6.46- 6.51 (m, 1H), 6.45 (d, J = 8.0Hz, 1H), 6.36 (d, J = 2.7 Hz, 1H), 3.93 (s, 3H), 3.36 (s, 3H), 3.00-3.06(m, 2H), 2.57-2.63 (m, 2H), 2.34 (s, 6H). calc 298.2, found 299.2 [MH]⁺6

2-(7-(furan- 3-yl)-4- methoxy-1- methyl-1H- indol-3-yl)- N,N-dimethylethan- amine 19 6-9 ¹H NMR (CDCl₃) δ (ppm) 7.40-7.51 (m, 2H),6.91 (d, J = 8.0 Hz, 1H), 6.67 (s, 1H), 6.51 (s, 1H), 6.45 (d, J = 7.7Hz, 1H), 3.92 (s, 3H), 3.46 (s, 3H), 3.01-3.07 (m, 2H), 2.58-2.64 (m,2H), 2.34 (s, 6H). calc 298.2, found 299.2 [MH]⁺ 6

2-(4- methoxy-1- methyl-7- (1H-pyrrol-2- yl)-1H-indol- 3-yl)-N,N-dimethylethan- amine 20 6-10 ¹H NMR (DMSO-d₆) (HCl salt) δ (ppm) 11.03(bs, 1H), 7.02 (s, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.54 (m, 1H), 6.54 (d,J = 7.7 Hz, 1H), 6.07- 6.11 (m, 1H), 6.59-6.63 (m, 1H), 3.90 (s, 3H),3.23 (s, 3H), 3.10-3.29 (m, 4H), 2.81-2.87 (m, 6H). calc 297.2, found298.2 [MH]⁺ 6

3-(3-(2- (dimethylamino)- ethyl)-4- methoxy-1- methyl-1H- indol-7-yl)prop-2-yn- 1-ol 21 6-11 ¹H NMR (CDCl₃) δ (ppm) 7.20 (d, J = 8.0 Hz,1H), 6.64 (s, 1H), 6.38 (d, J = 8.2 Hz, 1H), 4.53 (s, 2H), 4.04 (s, 3H),3.90 (s, 3H), 2.96- 3.02 (m, 2H), 2.53-2.59 (m, 2H), 2.32 (s, 6H). calc286.2, found 287.2 [MH]⁺ 6

3-(2- (dimethylamino)- ethyl)-4- methoxy-1- methyl-N- phenyl-1H-indol-7- amine 22 6-12 ¹H NMR (CDCl₃) δ (ppm) 7.13 (dd, J = 7.4, 8.5 Hz,2H), 6.85 (d, J = 8.2 Hz, 1H), 6.72 (tt, J = 1.1, 7.4 Hz, 1H), 6.63 (s,1H), 6.54 (dd, J = 1.1, 7.7 Hz, 2H), 6.40 (d, J = 8.0 Hz, 1H), 3.91 (s,3H), 3.75 (s, 3H), 3.00-3.06 (m, 2H), 2.57- 2.63 (m, 2H), 2.34 (s, 6H).calc 323.2, found 324.2 [MH]⁺ 6

2-(4- methoxy-1- methyl-7- (thiophen-3- yl)-1H-indol- 3-yl)-N,N-dimethylethan- amine 23 6-13 ¹H NMR (CDCl₃) δ (ppm) 7.33 (dd, J = 3.0,5.0 Hz, 1H), 7.20 (dd, J = 1.1, 2.9 Hz, 1H), 7.13 (dd, J = 1.1, 5.0 Hz,1H), 6.93 (d, J = 8.0 Hz, 1H), 6.66 (s, 1H), 6.47 (d, J = 8.0 Hz, 1H),3.93 (s, 3H), 3.27 (s, 3H), 3.02-3.08 (m, 2H), 2.59-2.65 (m, 2H), 2.35(s, 6H). calc 314.1, found 315.1 [MH]⁺ 6

2-(4- methoxy-1- methyl-7- (pyridin-3- yl)-1H-indol- 3-yl)-N,N-dimethylethan- amine 24 6-14 ¹H NMR (DMSO-d₆) (HCl salt) δ (ppm) 10.58(bs, 1H), 8.91 (s, 1H), 8.83 (d, J = 5.5 Hz, 1H), 8.37 (d, J = 8.3 Hz,1H), 7.91 (dd, J = 5.5, 8.3 Hz, 1H), 7.12 (s, 1H), 6.98 (d, J = 8.0 Hz,1H), 6.68 (d, J = 8.0 Hz, 1H), 3.95 (s, 3H), 3.26 (s, 3H), 3.17-3.24(bs, 4H), 2.82 (d, J = 5.0 Hz, 6H). calc 309.2, found 310.2 [MH]⁺ 6

Example 252-(1-benzyl-4-(benzyloxy)-7-fluoro-1H-indol-3-yl)-N,N-dimethylethanamine(7-2)

Following the procedure used to prepare compound 1-8c (step 7 scheme 1),compound 7-1 ((prepared according to J. Med. Chem. 2000, 43, 4701) gavecompound 7-2 (table 7).

Example 26 1-benzyl-3-(2-(dimethylamino)ethyl)-7-fluoro-1H-indol-4-ol(7-3)

Following the procedure used to prepare compound 1-9c (step 8 scheme 1),compound 7-2 gave compound 7-3 (table 7).

The compounds in table 7 were made according to processes described inscheme 1 and 7.

TABLE 7 Ex. ID Procedure Strucutre name number number NMR MS of scheme

2-(1-benzyl- 4- (benzyloxy)- 7-fluoro-1H- indol-3-yl)- N,N-dimethylethan- amine 25 7-2 ¹H NMR (CDCl₃) (HCl salt) δ (ppm) 12.10 (bs,1H), 7.40-7.50 (m, 5H), 7.26- 7.30 (m, 3H), 7.11-7.14 (m, 2H), 6.93 (s,1H), 6.77 (dd, J = 12.1, 8.3 Hz, 1H), 6.43 (dd, J = 8.5, 2.8 Hz, 1H),5.36 (s, 2H), 5.03 (s, 2H), 3.16-3.22 (m, 2H), 3.00- 3.07 (m, 2H), 2.23(s, 3H), 2.22 (s, 3H) calc 402.5, found 403.3 [MH]⁺ 7 Step 1

1-benzyl-3- (2- (dimethylamino)- ethyl)-7- fluoro-1H- indol-4-ol 26 7-3¹H NMR (DMSO-d₆) (HCl salt) δ (ppm) 10.04 (bs, 1H), 9.70 (bs, 1H),7.21-7.33 (m, 4H), 7.09-7.12 (m, 2H), 6.66 (dd, J = 12.4, 8.2 Hz, 1H),6.27 (dd, J = 8.5, 3.3 Hz, 1H), 5.38 (s, 2H), 3.28- 3.32 (m, 2H),3.14-3.19 (m, 2H), 2.80 (s, 6H) calc 312.3, found 313.2 [MH]⁺ 7

2-(4- (benzyloxy)- 7-fluoro-1- (thiophen-2- ylmethyl)- 1H-indol-3-yl)-N,N- dimethylethan- amine 27 7-4 ¹H NMR (CDCl₃) (HCl salt) δ (ppm)12.06 (bs, 1H), 7.41-7.49 (m, 5H), 7.20 (dd, J = 5.0, 1.1 Hz, 1H), 6.95-6.97 (m, 2H), 6.92 (dd, J = 5.0, 3.6 Hz, 2H), 6.80 (dd, J = 12.1, 8.5Hz, 1H), 6.44 (dd, J = 8.5, 2.8 Hz, 1H), 5.52 (s, 2H), 5.02 (s, 2H),3.17-3.19 (m, 2H), 2.99- 3.08 (m, 2H), 2.23 (s, 6H) calc 408.5, found409.0 [MH]⁺ 7 Step 1

3-(2- (dimethylamino)- ethyl)-7- fluoro-1- (naphthalen- 2-ylmethyl)-1H-indol-4-ol 28 7-5 ¹H NMR (CDCl₃) δ (ppm) 7.73-7.81 (m, 3H), 7.56 (s,1H), 7.43-7.46 (m, 2H), 7.30 (dd, J = 8.3, 1.7 Hz, 1H), 6.74 (s, 1H),6.72 (dd, J = 12.4, 8.2 Hz, 1H), 6.37 (dd, J = 8.5, 3.6 Hz, 2H), 5.53(s, 2H), 2.87-2.91 (m, 2H), 2.64-2.67 (m, 2H), 2.36 (s, 6H) calc 362.2,found 363.1 [MH]⁺ 7

2-(4- (benzyloxy)- 7-fluoro-1- (naphthalen- 2-ylmethyl)- 1H-indol-3-yl)-N,N- dimethylethan- amine 29 7-6 ¹H NMR (CDCl₃) (HCl salt) δ (ppm)12.10 (bs, 1H), 7.62-7.81 (m, 3H), 7.59 (s, 1H), 7.41-7.50 (m, 6H),7.26-7.29 (m, 1H), 7.00 (s, 1H), 6.77 (dd, J = 12.1, 8.5 Hz, 1H), 6.43(dd, J = 8.5, 2.7 Hz, 2H), 5.52 (s, 2H), 5.04 (s, 2H), 3.18-3.23 (m,2H), 2.98-3.12 (m, 2H), 2.23 (s, 6H) calc 452.2, found 453.1 [MH]⁺ 7Step 1

3-(2- (dimethylamino)- ethyl)-7- fluoro-1- (pyridin-2- ylmethyl)-1H-indol-4- ol 30 7-7 ¹H NMR (DMSO-d₆) (HCl salt) δ (ppm) 10.18 (bs,1H), 9.73 (s, 1H), 8.51 (d, J = 4.9 Hz, 1H), 7.72 (t, J = 7.4 Hz, 1H),7.27 (t, J = 5.2 Hz, 1H), 7.24 (s, 1H), 6.82 (d, J = 7.7 Hz, 1H), 6.64(dd, J = 12.6, 8.5 Hz, 1H), 6.28 (dd, J = 8.2, 3.0 Hz, 1H), 5.48 (s,2H), 3.29-3.36 (m, 2H), 3.16-3.21 (m, 2H), 2.79 (s, 6H) calc 313.2,found 314.2 [MH]⁺ 7

2-(4- (benzyloxy)- 7-fluoro-1- (pyridin-2- ylmethyl)- 1H-indol-3-yl)-N,N- dimethylethan- amine 31 7-8 ¹H NMR (CDCl₃) (HCl salt) δ (ppm)12.06 (bs, 1H), 8.63 (d, J = 4.4 Hz, 1H), 7.88 (t, J = 8.0 Hz, 1H),7.41-7.51 (m, 6H), 7.12 (s, 1H), 7.08 (d, J = 7.4 Hz, 1H), 6.77 (dd, J =12.1, 8.5 Hz, 1H), 6.46 (dd, J = 8.8, 3.0 Hz, 1H), 5.74 (s, 2H), 5.06(s, 2H), 3.18-3.24 (m, 2H), 3.06-3.11 (m, 2H), 2.32 (s, 3H), 2.30 (s,3H) calc 403.2, found 404.2 [MH]⁺ 7 Step 1

3-(2- (dimethylamino)- ethyl)-7- fluoro-1-(4- methoxybenzyl)- 1H-indol-4-ol 32 7-9 ¹H NMR (DMSO-d₆) (HCl salt) δ (ppm) 10.00 (bs, 1H), 9.69(bs, 1H), 7.23 (s, 1H), 7.09 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.5 Hz,2H), 6.66 (dd, J = 12.4, 8.3 Hz, 1H), 6.26 (dd, J = 8.5, 3.3 Hz, 1H),5.29 (s, 2H), 3.69 (s, 3H), 3.27-3.32 (m, 2H), 3.12-3.17 (m, 2H), 2.79(s, 6H) calc 342.4, found 343.2 [MH]⁺ 7

2-(4- (benzyloxy)- 7-fluoro-1- (4- methoxybenzyl)- 1H-indol- 3-yl)-N,N-dimethylethan- amine 33 7-10 ¹H NMR (CDCl₃) (HCl salt) δ (ppm) 12.11(bs, 1H), 7.38-7.50 (m, 5H), 7.10 (d, J = 8.8 Hz, 2H), 6.90 (s, 1H),6.82 (d, J = 8.5 Hz, 2H), 6.77 (dd, J = 12.1, 8.5 Hz, 1H), 6.42 (dd, J =8.3, 2.8 Hz, 1H), 5.29 (s, 2H), 5.03 (s, 2H), 3.77 (s, 3H), 3.15-3.20(m, 2H), 2.98- 3.06 (m, 2H), 2.23 (s, 3H), 2.21 (s, 3H) calc 433.2,found 433.2 [MH]⁺ 7 Step 1

Example 342-(7-fluoro-4-methoxy-1-methyl-5-phenyl-1H-indol-3-yl)-N,N-dimethylethanamine(8-13) Step 1: 2,6-dibromo-4-fluorophenol (8-2): prepared according toJ. Med. Chem. 1999, 42, 2007-2020

The solution of 8-1 (112.1 g, 1 mol) in acetic acid (1 L) was addedbromine (352 g, 2.2 mol) dropwise over an hour at room temperature.After addition, the mixture was stirred for another 2 h. The reactionmixture was poured onto crushed ice followed by the addition of 500 mLof saturated aqueous NaHSO₃. The white precipitate was filtered anddried to afford 8-2 (246.4 g, 91.3%) as a white solid.

Step 2: 1,3-dibromo-5-fluoro-2-methoxybenzene (8-3)

To the mixture of 8-2 (262.6 g, 0.973 mmol) and K₂CO₃ (215 g, 1.56 mol)in acetone (1.8 L) was added Me₂SO₄ (140.1 g, 1.17 mol) in acetone (300mL) dropwise via a constant pressure dropping funnel over 20 min. Themixture was stirred for 6 h at room temperature. TLC showed that thereaction was completed. The solid was filtered off and the filtrate wasconcentrated in vacuuo to get 8-3 (273.4 g, 99%) as a white solid whichwas used for the next step without further purification.

Step 3: 1,3-dibromo-5-fluoro-2-methoxy-4-nitrobenzene (8-4)

The solution of 8-3 (273.4 g, 0.963 mol) dissolved in concentrated H₂SO₄(1.6 L) at 0° C. The mixture of conc. HNO₃ (63.2 mL) and conc. H₂SO₄(400 mL) was added dropwise over 1 h. The color of the reaction becameorange. TLC monitored the starting material was disappeared. Thereaction mixture was poured onto crushed ice and extracted with ethylacetate (800 mL×3). The combined organic layers were combined and wereconcentrated in vacuuo to 400 mL, which was cooled under ice bath toafforded 8-4 (234.2 g, 73.9%) as a white solid.

Step 4: 2,4-dibromo-6-fluoro-3-methoxyaniline (8-5)

To the solution of 8-4 (234.2 g, 0.784 mol) and concentrated HCl (720mL) in ethanol (2.2 L) at room temperature, SnCl₂.H₂O (415 g, 2.0 mol)was added by portions. The mixture was stirred for 16 h. TLC showed thereaction was completed. The volatiles were removed in vacuuo. Theresidue was quenched with cooled water (500 mL) and ethyl acetate (1.5L). The aqueous layer was neutralized with KOH until PH=6˜7. The whiteprecipitate was filtered off to get a clear solution, which wasextracted with ethyl acetate (600 mL×3). The combined organic layerswere washed with brine twice, dried over anhydrous sodium sulfate. Afterfiltration and evaporation, 8-5 (212.7 g, 100%) was obtained as brownishwhite solid.

Step 5: N-(2,4-dibromo-6-fluoro-3-methoxyphenyl)acetamide (8-6)

Compound 8-5 (212.7 g, 0.711 mol) was added to acetic anhydride (200 mL)in one portion at 20° C. The reaction mixture was stirred for 30 minutesand then was filtered to get 8-6 (192 g, 79.2%) as a white solid.

Step 6: (Z)-ethyl4-(N-(2,4-dibromo-6-fluoro-3-methoxyphenyl)acetamido)but-2-enoate (8-7)

To the solution of 8-6 (1.3 g, 3.82 mmol) in THF (20 mL) at roomtemperature was added NaH (100 mg, 4.2 mmol, dispersed in mineral oil,60%). The mixture was stirred for 30 min until no gas was released.(E)-ethyl 4-brombut-2-enoate (0.88 g, 4.58 mmol) in THF (5 mL) wasadded. The mixture was stirred overnight at room temperature. TLC showedthat the reaction was completed. Water was added to the reaction mixtureand extracted with ethyl acetate (50 mL×3). The combined organic layerswere combined and were concentrated in vacuuo. The residue was purifiedby flash chromatography (silica gel, elution with ethylacetate/petroleum=1:8 to 1:2) to afford 8-7 (1.6 g, 92.4%) as yellowoil.

Step 7: ethyl2-(1-acetyl-5-bromo-7-fluoro-4-methoxy-H-indol-3-yl)acetate (8-8)

To the solution of 8-7 (20 g, 44.0 mmol) in anhydrous DMF (250 mL) wasadded Pd(OAc)₂ (2.0 g, 8.8 mmol), Bu₄NBr (14.3 g, 44.0 mmol) and DIPEA(14.2 g, 110 mmol) under N₂. The mixture was stirred at 80° C. for 3 h.TLC showed that the reaction was completed. The mixture was poured intoice water and extracted with ethyl acetate (150 mL×3). The organiclayers were combined and were concentrated in vacuuo. The residue waspurified by flash chromatography (Silica-gel, petroleum ether/ethylacetate=10:1) to afford 8-8 (13.0 g, 79%) as a white solid.

Step 8: 2-(5-bromo-7-fluoro-4-methoxy-H-indol-3-yl)acetic acid (8-9)

To the solution of 8-8 (16.5 g, 44.0 mmol) in water (50 mL) was added 4NKOH (50 mL). The mixture was stirred at room temperature for 1 h. TLCshowed that the reaction was completed. The mixture was neutralized withHCl to pH=5. The formed precipitate was collected and washed with water.After drying, 8-7 (11.5 g, 87%) was obtained as a yellowish solid.

Step 9:2-(5-bromo-7-fluoro-4-methoxy-H-indol-3-yl)-N,N-dimethylacetamide (8-10)

To the solution of 8-9 (11.5 g, 38.0 mmol) in THF (300 mL) was addedHATU (22.0 g, 58.0 mmol) Me₂NH.HCl (3.1 g, 38.0 mmol) at 0° C. After themixture was stirred for 5 minutes, DIPEA (12.3 g, 95.3 mmol) was added.The mixture was stirred overnight at room temperature. The volatile wasremoved and the residue was purified by flash chromatography (Silicagel, DCM/MeOH=50:1) to afford 8-10 (9.0 g, 72%) as white solid.

Step 10:2-(5-bromo-7-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)-N,N-dimethylacetamide(8-11)

To the solution of 8-10 (7.0 g, 21.3 mmol) in anhydrous DMF (20 mL) wasadded KOH (4.34 g, 78.0 mmol), and MeI (4.55 g, 32.0 mmol) at roomtemperature. After the mixture was stirred for 1 h, TLC showed that thereaction was completed. The mixture was quenched with water andextracted with ethyl acetate (150 mL×3). The organic layers werecombined and concentrated in vacuuo. 8-11 (7.2 g, crude) was obtained asyellow oil and used for the next step without further purification.

Step 11:2-(7-fluoro-4-methoxy-1-methyl-5-phenyl-1H-indol-3-yl)-N,N-dimethylacetamide(8-12)

To the solution of 8-11 (200 mg, 0.58 mmol) in dioxane (10 mL) was addedphenylboronic acid (86 mg, 0.70 mmol), Pd(PPh₃)₄ (68 mg, 0.06 mmol), andCs₂CO₃ (760 mg, 2.3 mmol) under nitrogen atmosphere. The reactionmixture was refluxed overnight, poured into water and extracted withethyl acetate (20 mL×3). The separated organic layer was dried overanhydrous sodium sulfate and concentrated in vacuuo. The residue waspurified by flash chromatography (elution with petroleum ether:ethylacetate=1:1) to afford 8-12 (160 mg, 81%) as white solid. LCMS: calc340.4 and found 341.1 [MH]⁺.

Step 12:2-(7-fluoro-4-methoxy-1-methyl-5-phenyl-1H-indol-3-yl)-N,N-dimethylethanamine(8-13)

Following the procedure used to prepare compound 1-7a (step 6 scheme 1),compound 8-12 gave compound 8-13

The compounds in table 8 were made according to processes described inscheme 8.

TABLE 8 Ex. ID Procedure Structure name number number NMR MS of scheme

2-(7-fluoro- 4-methoxy- 1-methyl-5- phenyl-1H- indol-3-yl)- N,N-dimethyl- ethanamine 34 8-13 1H NMR (CDCl3) δ (ppm) 7.52 (d, J = 7.2 Hz,2H), 7.36 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.2 Hz, 1H), 6.89 (s, 1H),6.82 (d, J = 8.8 Hz, 1H), 3.87 (s, 3H), 3.38 (s, 3H), 3.30 (s, 4H), 2.79(s, 6H) calc 326.4, found 327.1 [MH]+ 8

2-(5-bromo- 1-ethyl-7- fluoro-4- methoxy-1H- indol-3-yl)- N-phenyl-acetamide 35 8-14 1H NMR (CDCl3) δ (ppm) 8.58 (br. s, 1H), 7.45 (t, J =1.2 Hz, 2H), 7.26 (t, J = 6.4 Hz, 5H), 7.02-7.08 (m, 3H), 4.25 (q, J =7.2 Hz, 2H), 4.02 (s, 3H), 3.80 (s, 2H), 1.45 (t, J = 6.8 Hz, 3H) calc406.3, found 407.0 [MH]+ 8 Step 1-10

Example 36 2-(7-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)propan-1-amine(9-5) Step 1: methyl2-(5-bromo-7-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)propanoate (9-2)

To the solution of 9-1 (prepared according to the same procedure ofethyl 2-(5-bromo-7-fluoro-4-methoxy-1H-indol-3-yl)acetate) (2.0 g, 6.3mmol) in anhydrous DMF (15 mL) was added KOH (1.12 g, 20 mmol), andiodomethane (1.8 g, 12.7 mmol). The mixture was stirred for 1 h at roomtemperature. After quenching with water, the reaction mixture wasextracted with ethyl acetate (150 mL×3). The combined organic layerswere dried over anhydrous sodium sulfate. After filtration andconcentration, a residue 9-2 (3.0 g, crude) was obtained as yellow oilwhich was used for the next step without further purification.

Step 2: 2-(5-bromo-7-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)propanoicacid (9-3)

To the solution of 9-2 (0.5 g, 1.5 mmol) in water (10 mL) was added 2NKOH (10 mL). The mixture was stirred at room temperature for 1 h. Themixture was neutralized with HCl to pH: 5. The precipitate was filteredand dried. 9-3 (210 mg, crude) was obtained as a yellow solid.

Step 3: 2-(5-bromo-7-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)propanamide(9-4)

To the solution of 9-3 (150 mg, 0.45 mmol), HATU (260 mg, 0.68 mmol) andNH₄Cl (26 mg, 0.49 mmol) in THF (10 mL) was added DIPEA (147 mg, 0.57mmol) at 0° C. The mixture was stirred overnight at room temperature.The mixture was diluted with ethyl acetate (30 mL) and washed with brinetwice. The combined organic layers were dried over anhydrous sodiumsulfate. After filtration and concentration, the obtained residue waspurified by flash chromatography (Silica gel, DCM:MeOH) to afford 9-4(90 mg, 84%) as yellow oil.

Step 4: 2-(7-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)propan-1-amine(9-5)

To the solution of 9-4 (154 mg, 0.46 mmol) in anhydrous THF (10 mL) wasadded LiAlH₄ (53 mg, 1.40 mmol). The mixture was heated to reflux for 2h. Na₂SO₄.10H₂O was added and the solid was filtered off. The filtratewas concentrated in vacuuo to get a residue, which was purified bypreparative TLC (DCM:MeOH: 10:1) to afford compound 9-5 (30 mg, 27%yield) as white solid.

The compound in table 9 was made according to processes described inscheme 9.

TABLE 9 Ex. ID Procedure Structure name number number NMR MS of scheme

2-(7-fluoro- 4-methoxy-1- methyl-1H- indol-3- yl)propan-1- amine 36 9-51H NMR (DMSO-d6) δ (ppm) 6.79 (s, 1H), 6.73 (dd, J1 = 8.8 Hz, J2 = 9.4Hz, 1H), 6.27 (dd, J1 = 2.4 Hz, J2 = 6.5 Hz, 1H), 3.9 (d, J = 1.6 Hz,3H), 3.88 (s, 3H), 3.66-3.69 (m, 1H), 3.19- 3.23 (m, 1H), 3.02-3.12 (m,3H), 1.37 (d, J = 6.8 Hz, 3H), 1.25 (s, 1H). calc 236.3, found 237.1[MH]+ 9

Example 39 1-ethyl-6-fluoro-3-(2-morpholinoethyl)-1H-indol-4-ol (11-5)Step 1: methyl 2-(1-ethyl-6-fluoro-4-hydroxy-1H-indol-3-yl)acetate(11-2)

To a solution of 11-1 (15 g, 42.21 mmol) in dioxane (130 mL) was addedPd/C (10%, 3 g) and NaH₂PO₂ (21.5 g, 203 mmol in 21.5 mL of water). Themixture was heated to reflux for 6 days. After cooling, the mixture wasfiltered through a silica gel pad and washed with methanol (100 mL). Thefiltrate was concentrated in vacuuo to get a residue, which was purifiedby silica gel chromatography (elution with petroleum:ethyl acetate=2:1)to get 11-2 (5.4 g, 51%) as a white solid. LCMS: calc 251.3 and found251.9[MH]⁺.

Step 2: 2-(1-ethyl-6-fluoro-4-hydroxy-1H-indol-3-yl)acetic acid (11-3)

Following the procedure used to prepare compound 8-7 (step 8 scheme 8),NaOH was replaced by KOH, compound 11-2 gave compound 11-3.

Step 3:2-(1-ethyl-6-fluoro-4-hydroxy-1H-indol-3-yl)-1-morpholinoethanone (11-4)

To a solution of compounds 11-3 (119 mg, 0.5 mmol) in DMF (2 mL) wasadded morpholine (66 uL, 0.75 mmol), triethylamine (0.24 mL, 1.75 mmol)and BOP (265 mg, 0.6 mmol). The reaction mixture was stirred at roomtemperature overnight. The solution was diluted with water and extractedwith EtOAc. Combined organic layers were washed with 1N HCl, water,brine, dried over MgSO₄, filtered and concentrated. The crude materialwas purified by flash chromatography (silica gel, ethyl acetate:hexanes:25:75 to 100%) gave pure 11-4 (140 mg, 91%) as a white foam.

Step 4: 1-ethyl-6-fluoro-3-(2-morpholinoethyl)-1H-indol-4-ol (11-5)

Following the procedure used to prepare compound 1-7a (step 6 scheme 1),compound 11-4 gave compound 11-5 (41 mg, 27%) as a white solid.

The compounds in table 11 were made according to processes described inscheme 1 and 11.

TABLE 11 Ex. ID Procedure Structure name number number NMR MS of scheme

1-ethyl-6- fluoro-3-(2- mropholino- ethyl)-1H- indol-4-ol 39 11-5 (300MHz, DMSO-d6) δ (ppm) (HCl salt)- 10.61 (br. s, 1H), 10.17 (s, 1H), 7.05(s, 1H), 6.70 (dd, J = 10.2 and 2.1 Hz, 1H), 6.24 (dd, J = 11.4 and 2.1Hz, 1H), 4.04-3.94 (m, 4H), 3.76 (t, J = 11.7 Hz, 2H), 3.46 (d, J = 12.3Hz, 2H), 3.33 (br s, 2H), 3.19-3.06 (m, 4H), 1.26 (t, J = 7.2, 3H) calc292.4, found 293.0 [MH]+ 11

1-ethyl-6- fluoro-3-(2- (pyrrolidin-1- yl)ethyl)-1H- indol-4-ol 40 11-6(300 MHz, DMSO-d6) δ (ppm) (HCl salt) 10.41 (br. s, 1H), 10.20 (s, 1H),7.06 (s, 1H), 6.70 (dd, J = 10.2 and 2.1 Hz, 1H), 6.25 (dd, J = 11.4 and2.1 Hz, 1H), 4.01 (q, J = 7.2 Hz, 2H), 3.53 (br. s, 2H), 3.33 (br s,2H), 3.14- 3.00 (m, 4H), 1.98-1.86 (m, 4H), 1.26 (t, J = 7.2 Hz, 3H)calc 276.4 found 277.1 [MH]+ 11

1-ethyl-7- fluoro-3-(2- (phenyl- amino)ethyl)-1H- indol-4-ol 41 11-7(300 MHz, DMSO-d6) δ (ppm) 9.52 (s, 1H), 7.25- 6.63 (m, 8H), 6.22 (dd,J1 = 2.8 Hz, J2 = 6.2 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.39 (t, 2H, J= 7.2), 3.06 (t, 2H, J = 8.0), 1.32 (t, 3H, J = 7.2). calc 298.4, found299.1 [MH]+ 11

N-(2-(1- ethyl-7- fluoro-4- methoxy-1H- indol-3- yl)ethyl)aniline 4211-8 (300 MHz, DMSO-d6) δ (ppm) 7.14 (s, 1H), 7.07 (t, J = 8.0 Hz, 2H),6.80 (dd, J1 = 8.4 Hz, J2 = 9.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 2H), 6.50(t, J = 6.8 Hz, 1H), 6.37 (dd, J1 = 2.8 Hz, J2 = 6.3 Hz, 1H), 5.68 (t, J= 5.6 Hz, 1H), 4.21 (q, J = 6.8 Hz, 2H), 3.86 (s, 3H), 3.24 (q, J = 6.8Hz, 2H), 2.99 (t, J = 8.0 Hz, 2H), 1.31 (t, J = J = 6.8 Hz, 3H) calc312.4, found 313.0 [MH]+ 11

4-(2-(7- fluoro-4- methoxy-1- methyl-1H- indol-3- yl)ethyl) morpholine43 11-9 1H NMR (CDCl3) δ (ppm) 6.71 (dd, J1 = 8.4 Hz, J2 = 9.6 Hz, 2H),6.25 (dd, J1 = 2.8 Hz, J2 = 6.3 Hz, 1H), 3.89 (d, J = 1.6 Hz, 3H), 3.87(s, 3H), 3.82 (s, 4H), 3.08 (t, J = 6.8 Hz, 2H), 2.73 (s, 3H), 2.64 (s,3H). calc 292.4, found 293.1 [MH]+ 11

7-fluoro-4- methoxy-1- methyl-3-(2- (pyrrolidin-1- yl)ethyl)-1H- indole44 11-10 1H NMR (CDCl3) δ (ppm) 6.80 (s, 1H), 6.68 (dd, J1 = 8.4 Hz, J2= 9.1 Hz, 2H), 6.22 (dd, J1 = 2.8 Hz, J2 = 6.6 Hz, 1H), 3.83 (s, 6H),3.73-3.80 (m, 2H), 3.26- 3.37 (m, 4H), 2.86-2.87 (m, 2H), 1.99-2.18 (m,4H). calc 276.4, found 277.1 [MH]+ 11

1-ethyl-6- fluoro-3-(2- (2- methoxyethyl amino)ethyl)- 1H-indol-4-ol 44b11-11 1H NMR (300 MHz, MeOD) δ (ppm) 6.97 (s, 1H), 6.59 (dd, J = 9.9 and1.8 Hz, 1H), 6.21 (dd, J = 11.4 and 1.8 Hz, 1H), 4.05 (q, J = 7.2 Hz,2H), 3.62 (t, J = 4.5 Hz, 2H), 3.40-3.35 (m, 4H), 3.24-3.17 (m, 4H),1.38 (t, J = 7.2 Hz, 3H) Calc 280.16, found 281.1 [MH]+ 11

3-(2-(1,4- oxazepan-4- yl)ethyl)-1- ethyl-6- fluoro-1H- indol-4-ol 44c11-12 1H NMR (300 MHz, DMSO) δ (ppm) 11.10 (s, 1H), 6.94 (s, 1H), 6.63(dd, J = 10.2, 2.1 Hz, 1H), 6.13 (dd, J = 11.6, 2.2 Hz, 1H), 3.97 (q, J= 7.1 Hz, 2H), 3.76-3.51 (m, 4H), 2.88- 2.80 (m, 4H), 2.76-2.68 (m, 6H),2.41 (s, 2H), 1.88- 1.76 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H). calc 306.17,found 307.1 [MH]+ 11

3-(2-cis-2,6- dimethyl- morpholino) ethyl)-1-ethyl-6- fluoro-1H-indol-4-ol 44e 11-13 1H NMR (300 MHz, DMSO) δ (ppm) 10.69 (s, 1H), 6.94(s, 1H), 6.64 (dd, J = 10.2, 2.1 Hz, 1H), 6.13 (dd, J = 11.6, 2.1 Hz,1H), 3.97 (q, J = 7.1 Hz, 2H), 3.84-3.42 (m, 2H), 3.04- 2.67 (m, 4H),1.68 (t, J = 10.8 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H), 1.04 (d, J = 6.3Hz, 6H) calc 320.19, found 321.2 [MH]+ 11

3-(2-(3,3- difluoro- pyrrolidin-1- yl)ethyl)-1- ethyl-6- fluoro-1H-indol-4-ol 44f 11-14 1H NMR (300 MHz, DMSO) δ (ppm) 10.00 (s, 1H), 6.94(s, 1H), 6.64 (dd, J = 10.3, 2.1 Hz, 1H), 6.15 (dd, J = 11.6, 2.1 Hz,1H), 3.98 (q, J = 7.2 Hz, 2H), 3.01-2.80 (m, 4H), 2.80- 2.52 (m, 4H),2.33-2.10 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H). calc 312.14, found 313.1[MH]+ 11

1-ethyl-6- fluoro-3-(2- (piperazin-1- yl)ethyl)-1H- indol-4-ol 44g 11-151H NMR (300 MHz, MeOD-d6) δ (ppm) 6.83 (s, 1H), 6.52 (dd, J = 10.0, 2.1Hz, 1H), 6.15 (dd, J = 11.4, 2.1 Hz, 1H), 4.00 (q, J = 7.2 Hz, 2H),3.03-2.87 (m, 6H), 2.69 (t, J = 6.7 Hz, 2H), 2.59 (br. s, 4H), 1.35 (t,J = 7.2 Hz, 3H) calc 291.17, found 292.1 [MH]+ 11

Example 453-((1H-benzo[d]imidazol-2-yl)methyl)-1-ethyl-6-fluoro-1H-indol-4-ol(12-3) Step 1:N-(2-aminophenyl)-2-(1-ethyl-6-fluoro-4-hydroxy-1-H-indol-3-yl)acetamide (12-2)

The solution of 11-3 (440 mg, 1.85 mmol), HATU (850 g, 2.23 mmol),HNMe₂.HCl (150 g, 1.84 mmol) in THF (5 mL) was added DIPEA (600 mg, 4.63mmol) dropwise at 0° C.

The reaction temperature was allowed to raise room temperature andstirred overnight. The volatile was removed by evaporation. A whiteresidue was obtained, which was quenched with 100 mL of water andextracted with DCM (50 mL×4). The combined organic layers were driedover anhydrous Na₂SO₄. After filtration and concentration, the residuewas purified by silica gel chromatography (elution with petroleum:ethylacetate: 1:1) to get 12-2 (324 mg, 53.5%) as a white solid. LCMS: calc327.4 and found 328.1 [MH]⁺.

Step 2:3-((1H-benzo[d]imidazol-2-yl)methyl)-1-ethyl-6-fluoro-1H-indol-4-ol(12-3)

The solution of 12-2 (0.3 g, 0.92 mmol) in 25 mL of acetic acid washeated to 80° C. for 8 h. The volatile was removed in vacuuo and theresidue was neutralized with Na₂CO₃ solution to pH: 7. The mixture wasextracted with ethyl acetate (100 mL) and washed with brine. The organiclayer was dried over anhydrous Na₂SO₄. After filtration andconcentration, a residue was obtained, which was purified by preparativeTLC to give 12-3 (68 mg, 23.9%) The compounds in table 12 were madeaccording to processes described in scheme 1 and 12.

TABLE 12 Ex. ID Procedure Structure name number number NMR MS of scheme

3-((1H- benzo[d] imidazol-2- yl)methyl)- 1-ethyl-6- fluoro-1H-indol-4-ol 45 12-3 1H NMR (CDCl3) δ (ppm) 11.90 (br. s, 1H), 7.48 (dd,J1 = 3.2 Hz, J2 = 3.0 Hz, 2H), 7.14 (dd, J1 = 3.2 Hz, J2 = 4.8 Hz, 2H),7.06 (s, 1H), 6.73 (dd, J1 = 2.0 Hz, J2 = 7.8 Hz, 1H), 6.23 (dd, J1 =1.6 Hz, J2 = 9.7 Hz, 1H), 4.33 (s, 2H), 4.03 (q, J = 7.2 Hz, 2H), 1.26(q, J = 6.8 Hz, 3H) calc 309.3, found 310.1 [MH]+ 12

3- (benzo[d] oxazol-2- ylmethyl)- 1-ethyl-6- fluoro-1H- indol-4-ol 4612-4 1H NMR (CDCl3) δ (ppm) 7.67 (dd, J1 = 3.2 Hz, J2 = 4.2 Hz, 1H),7.50 (dd, J1 = 2.4 Hz, J2 = 3.7 Hz, 1H), 7.29-7.33 (m, 2H), 6.94 (s,1H), 6.54 (40, J1 = 1.8 Hz, J2 = 7.2 Hz, J3 = 7.4 Hz, 2H), 4.42 (s, 2H),3.99 (q, J = 7.2 Hz, 2H), 1.40 (t, 3H, J = 7.6 Hz) calc 310.3, found311.0 [MH]+ 12

Example 52 2-(6-fluoro-4-methoxy-1-(phenylsulfonyl)-1H-indol-3-yl)-N,N-dimethylethan amine (15-2) Step 1:2-(6-fluoro-4-methoxy-1-(phenylsulfonyl)-1H-indol-3-yl)-N,N-dimethylethan amine (15-2)

To the solution of 15-1 (100 mg, 0.42 mmol) in dry DMF (4 mL) was addedNaH (24 mg, 0.6 mmol, dispersed in mineral oil, 60%) in portions at 0°C. After stirring for 0.5 h, benzenesulfonyl chloride (148 mg, 0.84mmol) was added dropwise. After stirring for another 2 h, the mixturewas quenched with water and extracted with ethyl acetate. The combinedorganic layers were dried over anhydrous sodium sulfate. Afterfiltration and concentration, a yellow solid was obtained, which waspurified by flash chromatography (silica gel, DCM:MeOH 5%) to get 15-2(30 mg, 19%) as a white solid

TABLE 16 Ex. ID Procedure Structure name number number NMR MS of scheme

2-(6-fluoro- 4-methoxy-1- (phenylsulfonyl)- 1H-indol-3-yl)- N,N-dimethyl- ethanamine 52 15-2 1H NMR (CDCl3) δ (ppm): 7.86 (d, J = 7.6Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.46 (t, 2H, J = 8 Hz), 7.33 (dd, ,J1 = 2.0 Hz, J2 = 7.5 Hz, 1H), 7.25 (s, 1H), 6.43 (dd, J1 = 1.6 Hz, J2 =9.7 Hz, 1H), 3.86 (s, 3H), 3.05 (t, J = 7.2 Hz, 2H), 2.75 (t, J = 8 Hz,2H), 2.48 (s, 6H) calc 376.5, found 377.1 [MH]+ 15

Example 53 2-(6-fluoro-4-methoxy-1-(pyrimidin-2-yl)-1H-indol-3-yl)-N,N-dimethylethan amine (16.2) Step 1:2-(6-fluoro-4-methoxy-1-(pyrimidin-2-yl)-1H-indol-3-yl)-N,N-dimethylethan amine (16.2)

To the solution of 16-1 (94.4 mg, 0.4 mmol) in anhydrous DMF (4 mL) wasadded K₂CO₃ (124 mg, 0.9 mmol), CuO (0.27 g, 3.4 mmol) and2-chloropyrimidine (37.8 mg, 0.3 mmol). The mixture was heated to 120°C. and stirred as such for 3 h. After cooling, the reaction wasfiltered. The filtrate was diluted with 20 mL of water and extractedwith ethyl acetate (100 mL×3). The combined organic layers were washedwith brine and dried over anhydrous sodium sulfate. After filtration andconcentration, a yellow solid was obtained, which was purified by flashchromatography (silica gel, DCM:MeOH 5%) to give 16-2 (22.7 mg, 18.1%)

TABLE 17 Ex. ID Procedure Structure name number number NMR MS of scheme

2-(6-fluoro- 4-methoxy-1- (pyrimidin-2- yl)-1H-indol- 3-yl)-N,N-dimethyl- ethanamine 53 16-2 1H NMR (CDCl3) δ (ppm) 8.66 (d, J = 4.8 Hz,2H), 8.18 (dd, J1 = 1.6 Hz, J2 = 9.3 Hz, 1H), 7.89 (s, 1H), 7.02 (t, J =4.8 Hz, 1H), 6.46 (dd, J1 = 1.6 Hz, J2 = 9.7 Hz, 1H), 3.91 (s, 3H), 3.05(t, J1 = 7.6 Hz, 2H), 2.65 (t, J1 = 8.4 Hz, 2H), 2.36 (s, 6H). calc314.4, found 315.1 [MH]+ 16

Example 54N-Benzyl-2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethanamine (17-7)Step 1: Methyl2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-2-oxoacetate (17-2)

A solution of oxalyl chloride (0.8 mL, 9.37 mmol) in anhydrous ether (20mL) was added dropwise over 20 min to a 0° C. solution of 17-1 (2.0 g,6.247 mmol) (prepared according patent WO2009/103710) in anhydrous ether(20 mL). The reaction mixture was stirred at room temperature overnight,cooled to −20° C., and treated with a mixture of Et₃N in CH₃OH. Thereaction was diluted with EtOAc, washed with water and brine, and driedover Na₂SO₄. After concentration, the resulting residue wasrecrystallized from EtOAc to afford 17-2 as a white solid in 60% yield(1.5 g). ¹H NMR (300 MHz, CDCl₃) δ (ppm) 8.90 (br, 1H), 8.23 (d, J=3.3Hz, 1H), 7.51-7.53 (m, 2H), 7.28-7.35 (m, 4H), 5.18 (s, 2H), 3.80 (s,3H).

Step 2: 2-(4-(Benzyloxy)-5-fluoro-1H-indol-3-yl)ethanol (17-3)

A solution of 17-2 (1.98 g, 4.874 mmol) in dry 1,4-dioxane (80 mL) wasadded dropwise to a slurry of LiAlH₄ (1.85 g, 48.74 mmol) in dry1,4-dioxane (40 mL) at reflux. The mixture was held at reflux for 1 h.The mixture was then cooled, quenched with 2 mL H₂O, 2 mL NaOH (15%)solution, and 6 mL H₂O. After stirring for 20 min, the mixture wasfiltered and the filtrate was concentrated. The resulting residue waspurified by column chromatography on silica gel with hexanes/ethylacetate (1:0 to 1:1) as eluent to afford 17-3 as a colorless oil in 56%yield (1.0 g). ¹H NMR (300 MHz, CDCl₃) δ (ppm) 7.97 (br, 1H), 7.47-7.50(m, 2H), 7.34-7.43 (m, 3H), 6.96-6.98 (m, 3H), 5.27 (d, J=1.1 Hz, 2H),3.74 (dt, J=6.3, 6.0 Hz, 2H), 2.96 (t, J=6.3 Hz, 2H), 1.47 (t, J=6.3 Hz,1H). APCI [M+1]: 286.1

Step 3:4-(Benzyloxy)-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-fluoro-1-methyl-1H-indole(17-4)

To a solution of 17-3 (1.4 g. 4.907 mmol) in DMF (30 mL) were addedimidazole (2.67 g, 39.3 mmol) and TBDMSCl (2.96 g, 19.6 mmol) at roomtemperature. The reaction mixture was stirred overnight. The mixture wasconcentrated and the residue was diluted with EtOAc, washed with H₂O,brine, and dried over anhydrous Na₂SO₄. After concentration, the crudeproduct was used in the next step without purification.

To the above crude compound in DMF was added NaH (300 mg) at 0° C. andthe reaction mixture was stirred for 15 min. Methyl iodide (0.3 mL) wasadded, and then the mixture was stirred for 1 h. The mixture wasquenched with H₂O and concentrated. The residue was diluted with EtOAc,washed with H₂O, brine, dried over anhydrous Na₂SO₄. Afterconcentration, the residue was purified by column chromatography onsilica gel, eluting with Hexane/EtOAc (10%). A colorless oil 17-4 wasobtained in 79% yield (1.6 g).

¹H NMR (300 MHz, CDCl₃) δ (ppm) 7.48-7.51 (m, 2H), 7.31-7.39 (m, 3H),6.97 (dd, J=11.8, 8.8 Hz, 1H), 6.87 (dd, J=8.8, 3.6 Hz, 1H), 6.82 (s,1H), 5.22 (s, 2H), 3.77 (t, J=7.1 Hz, 2H), 3.68 (s, 3H), 3.00 (t, J=6.8Hz, 2H), 0.84 (s, 9H), 0.01 (s, 6H).

Step 4:3-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-5-fluoro-1-methyl-1H-indol-4-ol(17-5)

A mixture of 17-4 (454 mg, 1.098 mmol) and Pd(OH)₂/C in MeOH (0.5 mLNH₃) was hydrogenated at ambient pressure for 30 min at 25° C., then themixture was filtered through a plug of Celite and washed with EtOAc. Thecrude product was purified by column chromatography on silica geleluting with Hexane/EtOAc (20%) to afford a white solid 17-5 in 94%yield (334 mg). ¹H NMR (300 MHz, CDCl₃) δ (ppm) 8.27 (br, 1H), 6.96 (dd,J=10.9, 8.8 Hz, 1H), 6.73 (s, 1H), 6.68 (dd, J=8.8, 3.3 Hz, 1H), 3.90(t, J=5.2 Hz, 2H), 3.67 (s, 3H), 3.07 (t, J=5.5 Hz, 2H), 0.84 (s, 9H),0.01 (s, 6H). LRMS: calc 323.2 and found: 324.2 [M+1].

Step 5: 2-(5-Fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethanol (17-6)

At 0° C., NaH (529 mg, 13.23 mmol) was added to a solution of compound17-5 (2.14 g, 6.61 mmol) in DMF (30 mL). After 30 min, methyl iodide(0.6 mL, 9.92 mmol) was added, and then the reaction mixture was stirredfor 1 h. The mixture was quenched with H₂O and concentrated. The residuewas diluted with EtOAc, washed with H₂O, brine, and dried over anhydrousNa₂SO₄. After concentration, the crude product was used in the next stepwithout purification.

To the above crude compound in THF (30 mL) was added TBAF (10 mL) andthe reaction mixture was stirred for 4 h. The mixture was diluted withEtOAc, washed with H₂O, brine, dried over anhydrous Na₂SO₄. Afterconcentration, the residue was purified by column chromatography onsilica gel, eluting with Hexane/EtOAc (10%). A colorless oil 17-6 wasobtained in 90% yield (two steps), 1.3 g. ¹H NMR (300 MHz, CDCl₃) δ(ppm) 6.97 (dd, J=11.8, 8.8 Hz, 1H), 6.87 (dd, J=8.8, 3.3 Hz, 1H), 6.86(s, 1H), 4.04 (d, J=2.2 Hz, 3H), 3.87 (dt, J=6.1, 6.0 Hz, 2H), 3.70 (s,3H), 3.07 (t, J=6.3 Hz, 2H), 1.81 (t, J=5.6 Hz, 1H).

Step 6: N-Benzyl-2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethanamine(17-7)

MsCl (45 μL, 0.585 mmol) was added dropwise to a solution of compound17-6 (87 mg, 0.39 mmol) and Et₃N (0.2 mL, 1.56 mmol) in 10 mL CH₂Cl₂ at0° C. under N₂, and then the mixture was stirred at this temperature for2 h. TLC showed no more starting material left, and the reaction mixturewas diluted with CH₂Cl₂, and washed with brine. After drying the organiclayer with Na₂SO₄, the solvent was removed in vacuo, and the resultingcolorless oil used for the next step without purification.

A mixture of the mesylate intermediate, Na₂CO₃ (413 mg, 3.901 mmol), NaI(10 mg) and BnNH₂ (0.4 mL, 3.901 mmol) in 10 mL THF was heated to 80° C.overnight in a pressure bottle. After cooling to room temperature, thereaction mixture was diluted with H₂O and extracted with EtOAc (2×75mL). The combined organic phase was washed with brine and dried overNa₂SO₄. The residue was purified by column chromatography on silica gel,eluting with CH₂Cl₂/1% NH₄OH to afford 17-7 as colorless oil (80 mg,66%), which was converted to the hydrochloride salt. ¹H NMR (DMSO-d₆,300 MHz) δ (ppm) (HCl salt): 9.08 (br, 2H), 7.65 (dd, J=5.0, 1.1 Hz,1H), 7.32 (m, 1H), 7.18 (s, 1H), 7.08-7.13 (m, 2H), 7.04 (dd, J=11.8,8.8 Hz, 1H), 4.42 (br, 2H), 3.91 (d, J=2.2 Hz, 3H), 3.70 (s, 3H),3.1-3.18 (m, 4H). LRMS: calc 318.1. found 319.1[MH]+.

The compounds in Table 18 were made according to processes described inScheme 17.

TABLE 18 Ex. ID num- num- Procedure Structure name ber ber NMR MS ofscheme

8-chloro-3-(2- (5-fluoro-4- methoxy-1- methyl-1H- indol-3- yl)ethyl)-1-methyl- 2,3,4,5- tetrahydro- 1H-benzo [d]azepine 55 17-8 ¹H NMR(DMSO-d₆, 300 MHz) δ (ppm) (HCl salt): 10.64 (br, 1H), 7.30 (s, 1H),7.31-7.23 (m, 2H), 7.19 (s, 1H), 7.12-7.01 (m, 2H), 3.98 (d, J = 1.9 Hz,3H), 3.82-3.72 (m, 1H), 3.71 (s, 3H), 3.66- 3.58 (m, 1H), 3.56-3.40 (m,3H), 3.30-3.18 (m, 4H), 3.11-2.96 (m, 2H), 1.42 (d, J = 6.33 Hz, 3H)Calc 400.2 Found 401.1 (MH)⁺ 17

1-(2-(5- fluoro-4- methoxy-1- indol-3- yl)ethyl) pyrrolidine-2-carboxamide 56 17-9 ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm) (HCl salt): 9.52(brs, 1H), 8.19 (s, 1H), 7.86 (s, 1H), 7.21 (s, 1H), 7.12-7.00 (m, 2H),4.13 (m, 1H), 3.98 (d, J = 1.9 Hz, 3H), 3.80-3.71 (m, 1H), 3.70 (s, 3H),3.50-3.19 (m, 4H), 3.08 (t, J = 8.2 Hz, 2H), 2.11- 2.02 (m, 1H),1.96-1.86 (m, 2H) Calc 319.2 Found 320.1 (MH)⁺ 17

5-fluoro-4- methoxy-1- methyl-3-(2- (piperazin-1- yl)ethyl)-1H- indole57 17-10 ¹H NMR (D₂O, 300 MHz) δ (ppm) (HCl salt): 7.12- 7.14 (m, 2H),7.09 (dd, J = 15.7, 8.8 Hz, 1H), 4.01 (d, J = 1.6 Hz, 3H), 3.54 (br,8H), 3.41-3.46 (m, 2H), 3.21- 3.26 (m, 2H) calc 291.2 found 292.2 [MH]+17

2-(2-(5- fluoro-4- methoxy-1- methyl-1H- indol-3- yl)ethyl)- 1,2,3,4-tetrahydroiso- quinoline 59 17-12 ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm) (HClsalt): 10.69 (brs, 1H), 7.32-7.24 (m, 5H), 7.15-7.01 (m, 2H), 4.66 (m,1H), 4.45-4.34 (m, 1H), 3.99 (d, J = 1.9 Hz, 3H), 3.80-3.72 (m, 1H),3.71 (s, 3H), 3.49-3.20 (m, 6H), 3.09- 3.03 (m, 1H) Calc 338.2 Found339.1 [MH]⁺ 17

N-(2-(5- fluoro-4- methoxy-1- methyl-1H- indol-3- yl)ethyl)-4-phenylbutan- 1-amine 60 17-13 ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm) (HClsalt): 8.53 (br, 2H), 7.26-7.31 (m, 2H), 7.15-7.22 (m, 4H), 7.11 (dd, J= 8.8, 3.8 Hz, 1H), 7.04 (dd, J = 11.8, 8.8 Hz, 1H), 3.95 (d, J = 1.9Hz, 3H), 3.69 (s, 3H), 3.07-3.10 (m, 4H), 2.91-2.96 (m, 2H), 2.57-2.60(m, 2H), 1.60- 1.62 (m, 4H) calc 354.2 found 355.2 [MH]+ 17

5-fluoro-4- methoxy-1- methyl-3-(2- (4-phenyl- piperazin- 1-yl)ethyl)-1H-indole 61 17-14 ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm) (HCl salt): 10.72(br, 1H), 7.23-7.30 (m, 3H), 7.00-7.14 (m, 4H), 6.87 (t, J = 7.1 Hz,1H), 4.01 (d, J = 2.2 Hz, 3H), 3.82- 3.86 (m, 2H), 3.71 (s, 3H),3.65-3.68 (m, 2H), 3.33- 3.37 (m, 2H), 3.10-3.26 (m, 6H) calc 367.2found 368.1 [MH]+ 17

3-(2-(4-(3- chlorophenyl) piperazin-1- yl)ethyl)-5- fluoro-4- methoxy-1-methyl-1H- indole 62 17-15 ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm) (HCl salt):10.81 (br, 1H), 7.26 (dd, J = 16.2, 8.0 Hz, 1H), 7.22 (s, 1H), 7.04-7.13(m, 3H), 6.96-7.01 (m, 1H), 6.88 (dd, J = 7.4, 1.6 Hz, 1H), 4.01 (d, J =2.2 Hz, 3H), 3.90-3.93 (m, 2H), 3.71 (s, 3H), 3.63- 3.65 (m, 2H),3.31-3.36 (m, 2H), 3.16-3.25 (m 6H) calc 401.2 found 402.1 [MH]+ 17

(S)-N-(2-(5- fluoro-4- methoxy-1- methyl-1H- indol-3- yl)ethyl)-1,2,3,4- tetrahydro- naphthalen-1- amine 63 17-16 ¹H NMR (DMSO-d₆, 300MHz) δ (ppm) (HCl salt): 9.14 (br, 2H), 7.60 (d, J = 7.1 Hz, 1H),7.19-7.33 (m, 4H), 7.10 (dd, J = 8.8, 3.6 Hz, 1H), 7.03 (dd, J = 11.8,8.8 Hz, 1H), 4.52 (m, 1H), 3.92 (d, J = 1.9 Hz, 3H), 3.70 (s, 3H), 3.18(m, 4H), 2.70- 2.88 (m, 2H), 1.74-2.15 (m, 4H) calc 352.2 found 353.2[MH]+ 17

(R)-N-(2-(5- fluoro-4- methoxy-1- methyl-1H- indol-3- yl)ethyl)-1,2,3,4- tetrahydro- naphthalen-1- amine 64 17-17 ¹H NMR (DMSO-d₆, 300MHz) ppm (HCl salt): 9.19 (br, 2H), 7.61 (d, J = 7.1 Hz, 1H), 7.19-7.33(m, 4H), 7.10 (dd, J = 8.8, 3.8 Hz, 1H), 7.03 (dd, J = 11.8, 8.8 Hz,1H), 4.52 (m, 1H), 3.92 (d, J = 2.2 Hz, 3H), 3.70 (s, 3H), 3.12-3.21 (m,4H), 2.74-2.84 (m, 2H), 1.74- 2.16 (m, 4H) calc 352.2 found 353.2 [MH]+17

N-(2-(5- fluoro-4- methoxy-1- methyl-1H- indol-3- yl)ethyl)-3-(4-methyl- piperazin- 1-yl)aniline 65 17-18 ¹H NMR (D₂O, 300 MHz) δ(ppm) (HCl salt): 7.25-7.30 (m, 1H), 7.01-7.04 (m, 2H), 6.95 (s, 1H),6.87 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 8.0 Hz, 3H), 6.59 (m, 1H), 3.82(d, J = 1.1 Hz, 3H), 3.72 (t, J = 6.8 Hz, 2H), 3.59 (s, 3H), 3.53- 3.57(m, 4H), 3.10-3.17 (m, 4H), 2.90-2.96 (m, 2H), 2.90 (s, 3H) calc 396.2found 397.2 [MH]+ 17

5-fluoro-3- (2-(((6- methylpyridin- 2-yl)methyl) amino)ethyl)-1-propyl-1H- indol-4-ol 65a 17-19 ¹H NMR (D₂O, 300 MHz) δ (ppm) (HClsalt): 8.01 (t, J = 7.9 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.47 (d, J =7.7 Hz, 1H), 7.12 (s, 1H), 7.0 (dd, J = 10.9, 8.8 Hz, 1H), 6.9 (dd, J =9.1, 3.9 Hz, 1H), 4.42 (s, 2H), 3.99 (t, J = 6.9 Hz, 2H), 3.50 (t, J =6.6 Hz, 2H), 3.16 (t, J = 6.3 Hz, 2H), 2.50 (s, 3H), 1.73 (m, 2H), 0.77(t, J = 7.4 Hz, 3H) calc 341.2 found 342.2 [MH]+ 17 From 17-4 steps 5-2,6, 4

5-fluoro-1- methyl-3-(2- (((6-methyl- pyridin-2- yl)methyl)amino)ethyl)- 1H-indol-4-ol 65b 17-20 ¹H NMR (D₂O, 300 MHz) δ (ppm) (HClsalt): 8.02 (t, J = 7.9 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.47 (d, J =7.7 Hz, 1H), 7.03 (s, 1H), 7.0 (dd, J = 10.9, 9.1 Hz, 1H), 6.84 (dd, J =8.8, 3.3 Hz, 1H), 4.42 (s, 2H), 3.64 (s, 3H), 3.51 (t, J = 6.3 Hz, 2H),3.15 (t, J = 6.3 Hz, 2H), 2.51 (s, 3H) calc 313.2 found 314.2 [MH]+ 17From 17-4 steps 5-2, 6, 4

Example 662-(5-fluoro-1-methyl-4-phenethoxy-1H-indol-3-yl)-N,N-dimethylethanamine(18-2) Step 1: 2-(5-fluoro-1-methyl-4-phenethoxy-1H-indol-3-yl)ethanol(18-1)

To a solution of compound 17-5 (150 mg, 0.464 mmol) in DMF (10 mL) wasadded Cs₂CO₃ (181.5 mg, 0.557 mmol) and 2-bromoethylbenzene (70 μL,0.511 mmol). Then the reaction mixture was stirred at room temperatureovernight. The mixture was quenched with H₂O and concentrated. Theresidue was diluted with EtOAc, washed with H₂O, brine, and dried overanhydrous Na₂SO₄. After concentration, the crude product was used in thenext step without purification.

To the above crude compound in THF (10 mL) was added TBAF (3.0 mL) andthe reaction mixture was stirred for 4 h. The mixture was diluted withEtOAc, washed with H₂O, brine, and dried over anhydrous Na₂SO₄. Afterconcentration, the residue was purified by column chromatography,eluting with Hexane/EtOAc (30%) to afford 18-1 as a colorless oil (78mg, 54% yield). ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.29-7.32 (m, 5H), 6.96(dd, J=12.1, 9.1 Hz, 1H), 6.85 (dd, J=8.8, 3.6 Hz, 1H), 6.81 (s, 1H),4.46 (dt, J=6.9, 1.4 Hz, 2H), 3.68 (dt, J=6.3, 6.1 Hz, 2H), 3.67 (s,3H), 3.15 (t, J=7.1 Hz, 2H), 2.82 (t, J=6.3 Hz, 2H), 1.54 (t, J=6.3 Hz,1H).

Step 2:2-(5-fluoro-1-methyl-4-phenethoxy-1H-indol-3-yl)-N,N-dimethylethanamine(18-2)

Following the procedure (step 6, scheme 17) used to prepare compound17-7, compound 18-1 gave compound 18-2 in 72% yield as a colorless oil,which was converted to the hydrochloride salt. ¹H NMR (DMSO-d₆, 300 MHz)δ (ppm) (HCl salt): 9.92 (br, 1H), 7.23-7.32 (m, 5H), 7.21 (s, 1H), 7.10(dd, J=9.1, 4.1 Hz, 1H), 7.04 (dd, J=12.1, 8.8 Hz, 1H), 4.40 (td, J=7.4,1.6 Hz, 2H), 3.70 (s, 3H), 3.16-3.21 (m, 2H), 3.11 (t, J=7.1 Hz, 2H),3.00-3.06 (m, 2H), 2.73 (s, 6H). LRMS: calc 340.2. found 341.2

[MH]+.

The compounds in Table 19 were made according to processes described inScheme 18.

TABLE 19 Ex. ID Procedure Structure name number number NMR MS of scheme

2-(4-((4- chlorobenzyl) oxy)-5- fluoro-1- propyl-1H- indol-3-yl)ethanamine 66b 18-3 ¹H NMR (DMSO-d6, 300 MHz) δ (ppm) (HCl salt):7.73 (br, 3H), 7.51 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.22(s, 1H), 7.18 (dd, J = 9.1, 3.6 Hz, 1H), 7.03 (dd, J = 12.1, 8.8 Hz,1H), 5.19 (s, 2H), 4.03 (t, J = 6.9 Hz, 2H), 3.01 (br, 4H), 1.72 (m,2H), ), 0.83 (t, J = 7.1 Hz, 3H) calc 360.1 found 361.1 [MH]⁺ 18 Step 1from N1Pr of 17-5 19 Step 1 and 3

Example 673-(2-Aminoethyl)-5-fluoro-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indol-4-ol(19-3b) Step 1: 3-(2-Azidoethyl)-4-(benzyloxy)-5-fluoro-1H-indole (19-1)

Following the procedure (step 6, scheme 17) used to prepare compoundmesylate intermediate; compound 17-3 gave the mesylte analog used forthe next step without purification.

A mixture of the mesylate intermediate, NaN₃ (131 mg, 2.018 mmol) in 10mL DMF was heated at 80° C. overnight. After cooling to roomtemperature, the reaction mixture was diluted with H₂O and extractedwith EtOAc (2×75 mL). The combined organic phase was washed by brine anddried over Na₂SO₄. The crude was purified by flash columnchromatography, eluting with Hexane/EtOAc (10%) to give the product 19-1in 80% yield as a colorless oil. ¹H NMR (CDCl₃, 300 MHz) ppm: 7.94 (br,1H), 7.45-7.47 (m, 2H), 7.34-7.41 (m, 3H), 6.95-6.99 (m, 3H), 5.27 (d,J=1.1 Hz, 2H), 3.42 (t, J=7.1 Hz, 2H), 2.98 (t, J=6.9 Hz, 2H).

Step 2:3-(2-Azidoethyl)-4-(benzyloxy)-5-fluoro-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indole(19-2)

Following the procedure (step 5, scheme 17, TBAF deprotection stepunnecessary) used to prepare compound 17-6, compound 19-1 gave compound19-2 in 82% yield as a colorless oil. ¹H NMR (CDCl₃, 300 MHz) δ (ppm):7.25-7.47 (m, 5H), 6.91-6.97 (m, 3H), 3.91-4.04 (m, 3H), 3.58 (m, 1H),3.36-3.43 (m, 3H), 2.97 (t, J=6.9 Hz, 2H), 1.23-1.48 (m, 6H).

Step 3:3-(2-Aminoethyl)-5-fluoro-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indol-4-ol(19-3)

Following the procedure (step 4, scheme 17) used to prepare compound17-5, compound 19-2 was used as starting material, using Pd(OH)₂/C(20%)as source of Pd to afford 19-3 (45% yield) as a white solid. Thecompound was then converted to the hydrochloride salt. H NMR (D₂O, 300MHz) δ (ppm) (HCl salt): 7.06 (s, 1H), 7.03 (dd, J=11.2, 9.1 Hz, 1H),6.89 (dd, J=9.1, 3.6 Hz, 1H), 4.10 (dd, J=15.1, 4.1 Hz, 1H), 4.04 (dd,J=15.1, 7.7 Hz, 1H), 3.75-3.84 (m, 2H), 3.27-3.36 (m, 3H), 3.12-3.17 (m,2H), 1.63-1.79 (m, 2H), 1.40-1.50 (m, 3H), 1.20-1.28 (m, 1H). LRMS: calc292.2. found 293.1[MH]⁺.

The compounds in Table 20 were made according to processes described inScheme 19.

TABLE 20 Ex. ID Procedure Structure name number number NMR MS of scheme

3-(2- aminoethyl)- 5-fluoro-1- (2-phenoxy- ethyl)-1H- indol-4-ol 68a19-4 ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm) (HCl salt): 9.63 (br, 1H), 7.88(br, 2H), 7.25 (dd, J = 8.5, 7.7 Hz, 2H), 7.18 (s, 1H), 6.86-7.00 (m,5H), 4.43 (t, J = 5.2 Hz, 2H), 4.23 (t, J = 5.0 Hz, 2H), 3.07 (br, 4H)calc 314.1 found 315.1 [MH]+ 19

3-(2- aminoethyl)- 1-((2,3- dihydrobenzo [b][1,4] dioxin-2- yl)methyl)-5-fluoro-1H- indol-4-ol 68b 19-5 1H NMR (D₂O, 300 MHz) δ (ppm) (HClsalt): 7.03 (s, 1H), 6.97 (dd, J = 11.3, 9.1 Hz, 1H), 6.83-6.87 (m, 3H),6.72-6.78 (m, 2H), 4.55 (m, 1H), 4.30 (d, J = 5.8 Hz, 2H), 4.22 (dd, J =11.8, 2.5 Hz, 1H), 3.97 (dd, J = 11.8, 5.0 Hz, 1H), 3.25 (t, J = 7.4 Hz,2H), 3.11 (t, J = 6.6 Hz, 2H) calc 342.1 found 343.1 [MH]+ 19

2-(3-(2- aminoethyl)- 5-fluoro-4- hydroxy-1H- indol-1-yl)- N,N- diethyl-acetamide 68c 19-6 1H NMR (DMSO-d6, 300 MHz) δ (ppm) (HCl salt): 8.03(brs, 3H), 7.04 (s, 1H), 6.95 (dd, J = 11.2 Hz, 8.79 Hz, 1H), 6.68 (dd,J = 8.79 Hz, 3.5 Hz, 1H), 4.97 (s, 2H), 3.44-3.35 (m, 2H), 3.31-3.22 (m,2H), 3.07 (s, 4H), 1.18 (t, J = 8.0 Hz, 3H), 1.03 (t, J = 7.0 Hz, 3H)calc 307.2 found 308.2 [MH]+ 19

2-(3-(2- aminoethyl)- 5-fluoro-4- hydroxy-1H- indol-1- yl)acetamide 68d19-7 1H NMR (DMSO-d6, 300 MHz) δ (ppm) (HCl salt): 9.67 (s, 1H), 7.84(brs, 3H), 7.34 (s, 1H), 7.26 (s, 1H), 7.06 (s, 1H), 6.99 (dd, J = 11.5Hz, 8.79 Hz, 1H), 6.73 (dd, J = 8.79 Hz, 3.5 Hz, 1H), 4.65 (s, 2H),3.16-3.02 (m, 4H). Calc 251.1 Found 252.1 (MH)+ 19

Example 70N-Benzyl-2-(1-ethyl-7-fluoro-4-methoxy-1H-indol-3-yl)ethanamine (20-4)Step 1: 2-(7-Fluoro-4-methoxy-H-indol-3-yl)ethanol (20-2)

Following the procedure (step 2, scheme 17) used to prepare compound17-3, compound 20-1 (prepared according to Scheme 8) gave compound 20-2in 99% yield as a colorless oil. ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.97(s, 1H), 6.77 (dd, J=10.4, 8.5 Hz, 1H), 6.31 (dd, J=8.5, 3.3 Hz, 1H),3.92 (s, 3H), 3.86 (dt, J=6.0, 5.8 Hz, 2H), 3.11 (t, J=6.0 Hz, 2H).

Step 2: 2-(1-Ethyl-7-fluoro-4-methoxy-1H-indol-3-yl)ethanol (20-3)

To a solution of 20-2 (76 mg. 0.363 mmol) in DMF (5 mL) were addedimidazole (190 mg, 2.906 mmol) and TBDMSCl (220 mg, 1.453 mmol) at roomtemperature. The reaction mixture was stirred overnight. The mixture wasconcentrated and the residue was diluted with EtOAc, washed with H₂O,brine, and dried over anhydrous Na₂SO₄. After concentration, the crudeproduct was used in the next step without purification.

To the above crude compound in DMF (10 mL) was added NaH (31 mg, 0.774mmol) at 0° C. and the reaction mixture was stirred for 15 min. Ethyliodide (46 μL, 0.581 mmol) was added, and then the mixture was stirredfor 1 h. The mixture was quenched with H₂O and concentrated. The residuewas diluted with EtOAc, washed with H₂O, brine, dried over anhydrousNa₂SO₄. After concentration, the crude compound was dissolved in THF (5mL) and TBAF (2 mL) was added at room temperature. The reaction mixturewas stirred for 2 h, and then the mixture was diluted with EtOAc, washedwith H₂O, brine, dried over anhydrous Na₂SO₄. After concentration, theresidue was purified by column chromatography, eluting with hexane/EtOAc(50%). A colorless oil 20-3 was obtained in 77% yield, 66 mg.

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.80 (s, 1H), 6.73 (dd, J=12.4, 8.5 Hz,1H), 6.27 (dd, J=8.5, 3.0 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 3.82-3.87 (m,5H), 3.08 (t, J=6.1 Hz, 2H), 1.84 (t, J=5.8 Hz, 1H), 1.41 (t, J=7.1 Hz,3H).

Step 3: N-Benzyl-2-(1-ethyl-7-fluoro-4-methoxy-1H-indol-3-yl)ethanamine(20-4)

Following the procedure (step 6, scheme 17) used to prepare compound17-7, compound 20-3 was used as starting material, giving compound 20-4in 68% yield as a white solid, which was converted to the hydrochloridesalt. ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm) (HCl salt): 9.25 (br, 2H),7.54-7.57 (m, 2H), 7.42-7.44 (m, 3H), 7.16 (s, 1H), 6.82 (dd, J=12.4,8.5 Hz, 1H), 6.35 (dd, J=8.5, 2.7 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 4.17(s, 2H), 3.75 (s, 3H), 3.12 (br, 4H), 1.32 (t, J=7.1 Hz, 3H). LRMS: calc326.2. found 327.2 [MH]⁺.

The compounds in Table 21 were made according to processes described inScheme 20.

TABLE 21 Ex. ID Procedure Structure name number number NMR MS of scheme

2-(1-ethyl-7- fluoro-4- methoxy-1H- indol-3-yl)- N- phenylethyl-ethanamine 72 20-7 ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm) (HCl salt): 8.91(br, 2H), 7.25-7.37 (m, 5H), 7.17 (s, 1H), 6.83 (dd, J = 12.6, 8.5 Hz,1H), 6.39 (dd, J = 8.5, 2.5 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.84 (s,3H), 3.10-3.19 (m, 6H), 2.93- 2.99 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H)calc 340.2 found 341.2 [MH]+ 20

2-(1-ethyl-7- fluoro-4- methoxy-1H- indol-3-yl)- N-(1- phenylethyl)ethanamine 73 20-8 ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm) (HCl salt): 9.43(br, 2H), 9.07 (br, 1H), 7.52-7.54 (m, 2H), 7.39- 7.46 (m, 3H), 7.12 (s,1H), 6.79 (dd, J = 12.6, 8.3 Hz, 1H), 6.30 (dd, J = 8.8, 3.0 Hz, 1H),4.38 (br, 1H), 4.18 (q, J = 7.4 Hz, 2H), 3.66 (s, 3H), 2.82-3.05 (m,4H), 1.58 (d, J = 6.3 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H) calc 340.2 found341.2 20

2-(1-ethyl-7- fluoro-4- methoxy-1H- indol-3-yl)- N-(2-methyl- benzyl)ethanamine 74 20-9 ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm) (HCl salt): 8.97(br, 2H), 7.46-7.48 (m, 1H), 7.26-7.31 (m, 3H), 7.18 (s, 1H), 6.83 (dd,J = 12.4, 8.3 Hz, 1H), 6.37 (dd, J = 8.8, 3.0 Hz, 1H), 4.21 (q, J = 6.9Hz, 2H), 4.17 (s, 2H), 3.79 (s, 3H), 3.11-3.20 (m, 4H), 2.37 (s, 3H),1.32 (t, J = 7.1 Hz, 3H) calc 340.2 found 341.2 [MH]+ 20

N-(2-chloro- benzyl) 2-(1-ethyl- 7-fluoro-4- methoxy-1H- indol-3-yl)ethanamine 75 20-10 ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm) (HCl salt): 9.19(br, 2H), 7.69-7.72 (m, 1H), 7.55-7.58 (m, 1H), 7.44-7.47 (m, 2H), 7.18(s, 1H), 6.82 (dd, J = 12.6, 8.5 Hz, 1H), 6.37 (dd, J = 8.8, 3.0 Hz,1H), 4.30 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 3.11-3.19 (m,4H), 1.32 (t, J = 6.9 Hz, 3H) calc 360.1 found 361.1 [MH]+ 20

Example 772-(7-Fluoro-4-methoxy-1-methyl-5-phenyl-1H-indol-3-yl)-N-methylethanamine(22-5) Step 1: Methyl2-(7-fluoro-4-methoxy-5-phenyl-1H-indol-3-yl)acetate (22-2)

Following the procedure for preparing the compound 6-6 in (Step 5,Scheme 6), using 22-1 (prepared according to Scheme 8 but RCOOMe inplace of RCOOEt), phenylboronic acid, sodium carbonate and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in amicrowave reactor (150° C., 30 min) to give 22-2 as a white solid (93%).¹H NMR (CDCl₃) 6 (ppm) 8.24 (bs, 1H), 7.58-7.62 (m, 2H), 7.38-7.44 (m,2H), 7.30-7.35 (m, 1H), 7.15 (d, J=2.2 Hz, 1H), 6.89 (d, J=11.3 Hz, 1H),3.96 (s, 2H), 3.73 (s, 3H), 3.37 (s, 3H).

Step 2: 2-(7-Fluoro-4-methoxy-5-phenyl-1H-indol-3-yl)ethanol (22-3)

Following the procedure (step 2, scheme 17) used to prepare compound17-3, compound 22-2 gave compound 22-3 in 69% yield as a white solid. ¹HNMR (CDCl₃) δ ppm: 8.21 (bs, 1H), 7.58-7.62 (m, 2H), 7.39-7.45 (m, 2H),7.30-7.35 (m, 1H), 7.08 (d, J=2.5 Hz, 1H), 6.91 (d, J=11.3 Hz, 1H), 3.95(q, J=6.0 Hz, 2H), 3.45 (s, 3H), 3.13 (t, J=6.0 Hz, 2H), 2.14 (t, J=5.5Hz, 1H).

Step 3: 2-(7-Fluoro-4-methoxy-1-methyl-5-phenyl-1H-indol-3-yl)ethanol(22-4)

Following the procedure (step 2, scheme 20) used to prepare compound20-3, compound 22-3 gave compound 22-4 in 90% yield as a colorless oil.¹H NMR (CDCl₃) δ ppm: 7.58-7.62 (m, 2H), 7.39-7.45 (m, 2H), 7.30-7.35(m, 1H), 6.88 (s, 1H), 6.83 (d, J=1.9 Hz, 1H), 3.94 (d, J=1.9 Hz, 3H),3.87-3.92 (m, 2H), 3.43 (s, 3H), 3.08 (t, J=6.1 Hz, 2H), 2.15 (t, J=5.5Hz, 1H).

Step 4:2-(7-fluoro-4-methoxy-1-methyl-5-phenyl-1H-indol-3-yl)-N-methylethanamine(22-5)

Following the procedure (step 6, scheme 17) used to prepare compound17-7, compound 22-4 was used as starting material, giving compound 22-5in 47% yield as a colorless oil, which was converted to thehydrochloride salt. ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm) (HCl salt): 8.63(br, 2H), 7.57-7.60 (m, 2H), 7.45 (t, J=7.4 Hz, 2H), 7.30-7.36 (m, 1H),7.23 (s, 1H), 6.93 (d, J=12.9 Hz, 1H), 3.90 (d, J=1.9 Hz, 3H), 3.36 (s,3H), 3.16-3.21 (m, 2H), 3.06-3.11 (m, 2H), 2.59 (s, 3H). LRMS: calc312.2. found 313.1 [MH]⁺.

Example 782-(7-Fluoro-4-methoxy-1-methyl-5-phenethyl-1H-indol-3-yl)-N-methylethanamine(23-4) Step 1: Methyl2-(7-fluoro-4-methoxy-5-(phenylethynyl)-1H-indol-3-yl)acetate (23-1)

A mixture of 22-1 (358 mg, 1.0 mmol), phenylacetylene (0.55 mL, 5.0mmol), Pd(dppf)Cl₂. CH₂Cl₂ (163 mg, 0.2 mmol), CuI (38 mg, 0.2 mmol) in10 mL Et₃N was heated at 110° C. overnight under nitrogen. The reactionmixture was concentrated to dryness and purified by flash columnchromatography, eluting with hexanes/EtOAc to afford 23-1 as a brown oil(530 mg).

Step 2: 2-(7-Fluoro-4-methoxy-5-phenethyl-1H-indol-3-yl)ethanol (23-2)

A mixture of compound 23-1 (530 mg) and Pd/C (5%, 300 mg) in 100 mL ofMeOH/EtOAc (1:1) was stirred at room temperature overnight. The mixturewas filtered through Celite and concentrated to obtain a brown oil (460mg), which was used in the next step without purification.

To a solution of the intermediate (460 mg) in 20 mL dioxane, LiAlH₄ (380mg, 10 mmol) was added and the resulting mixture was heated to refluxfor 2 h. After cooled to 0° C., the mixture was quenched by water, 15%NaOH and water, then filtered and dried over Na₂SO₄. After theconcentration, the black oil was purified by flash column chromatographyeluting with hexanes/EtOAc to afford 23-2 as a brown oil (246 mg, 79%).¹H NMR (CDCl₃) δ ppm: 8.15 (bs, 1H), 7.18-7.32 (m, 5H), 7.03 (d, J=2.2Hz, 1H), 6.75 (d, J=11.3 Hz, 1H), 3.87-3.94 (m, 2H), 3.78 (s, 3H),2.89-3.04 (m, 4H), 2.12 (t, J=5.8 Hz, 1H).

Step 3: 2-(7-Fluoro-4-methoxy-1-methyl-5-phenethyl-1H-indol-3-yl)ethanol(23-3)

Following the procedure (step 2, scheme 20) used to prepare compound20-3, compound 23-2 gave compound 23-3 in 69% yield as a colorless oil.¹H NMR (CDCl₃, 300 MHz) δ ppm: 7.22-7.29 (m, 5H), 6.79 (s, 1H), 6.70 (d,J=12.9 Hz, 1H), 3.90 (d, J=1.92 Hz, 3H), 3.84-3.89 (m, 2H), 3.74 (s,3H), 3.05 (d, J=6.0 Hz, 2H), 2.9-2.96 (m, 4H), 2.11 (t, J=5.8 Hz, 1H).

Step 4:2-(7-Fluoro-4-methoxy-1-methyl-5-phenethyl-1H-indol-3-yl)-N-methylethanamine(23-4)

Following the procedure (step 6, scheme 17) used to prepare compound17-7, compound 23-3 was used as starting material, giving compound 23-4in 62% yield as a colorless oil, which was converted to thehydrochloride salt. ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm) (HCl salt): 8.62(br, 2H), 7.18-7.31 (m, 5H), 7.15 (s, 1H), 6.87 (d, J=13.4 Hz, 1H), 3.85(d, J=1.7 Hz, 3H), 3.69 (s, 3H), 3.05-3.13 (m, 4H), 2.88 (br, 4H), 2.57(s, 3H). LRMS: calc 340.2. found 341.1 [MH]⁺.

The compounds in Table 24 was made according to processes described inScheme 23.

TABLE 24 Ex. ID Procedure Structure name number number NMR MS of scheme

2-(5-(2- cyclohexyl ethyl)-7- fluoro-4- methoxy- 1-methyl- 1H-indol-3-yl)-N- methyl- ethanamine 79 23-5 ¹H NMR (DMSO-d₆, 300 MHz) δ (ppm)(HCl salt): 8.66 (br, 2H), 7.14 (s, 1H), 6.75 (d, J = 13.5 Hz, 1H), 3.85(d, J = 1.6 Hz, 3H), 3.72 (s, 3H), 3.05-3.16 (m, 4H), 2.58-2.63 (m, 2H),2.57 (s, 3H), 1.64-1.78 (m, 5H), 1.41-1.48 (m, 2H), 1.14-1.25 (m, 4H),0.89- 0.97 (m, 2H) calc 346.2 found 347.2 [MH]+ 23

Example 802-(4-(benzyloxy)-7-fluoro-1-(furan-2-ylmethyl)-1H-indol-3-yl)-N,N-dimethylethanamine(24-1) Step 1:2-(4-(benzyloxy)-7-fluoro-1-(furan-2-ylmethyl)-1H-indol-3-yl)-N,N-dimethylethanamine(24-1)

Following the procedure (step 5-1, scheme 17) used to prepare compound17-6, the compound 1-7c, gave compound 24-1 in 40% yield as a colorlessoil, which was converted to the hydrochloride salt. ¹H NMR (CDCl₃, 300MHz) δ (ppm) (HCl salt): 12.09 (br, 2H), 7.34-7.49 (m, 6H), 6.94 (s,1H), 6.88 (dd, J=12.1, 8.3 Hz, 1H), 6.43 (dd, J=8.8, 3.0 Hz, 1H),6.29-6.30 (m, 2H), 5.33 (s, 2H), 5.02 (s, 2H), 3.15-3.20 (m, 2H),3.00-3.04 (m, 2H), 2.23 (s, 3H), 2.22 (s, 3H). LRMS: calc 392.2. found393.2 [MH]⁺.

Example 822-(4-Methoxy-1-methyl-7-(phenylsulfonyl)-1H-indol-3-yl)-N,N-dimethylethanaminehydrochloride (25-1) Step 1:2-(4-Methoxy-1-methyl-7-(phenylsulfonyl)-1H-indol-3-yl)-N,N-dimethylethanaminehydrochloride (25-1)

A mixture of compound 6-5 (100 mg, 0.32 mmol), sodium benzenesulfinate(264 mg, 1.6 mmol), CuI (306 mg, 1.6 mmol) in 10 mL NMP was heated at150 OC for 3 h under argon. After cooling to room temperature, thereaction mixture was diluted with MeOH and filtered. The filtrate wasconcentrated and purified by flash column chromatography, eluting withCH₂Cl²/MeOH/NH₄OH to give the product as a brown oil (35 mg), which wasconverted to the HCl salt to afford 25-1 as a yellow solid (32 mg), mp200-203° C. ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 7.92 (d, J=8.5 Hz, 1H),7.77-7.82 (m, 2H), 7.47-7.61 (m, 3H), 6.83 (s, 1H), 6.59 (d, J=8.5 Hz,1H), 4.06 (s, 3H), 3.77 (s, 3H), 3.42 (bs, 2H), 3.26 (bs, 2H), 2.84 (bs,6H).

LRMS: Calc 372.2. found 373.2 [MH]⁺.

Example 83 (E)-Methyl3-(3-(2-(dimethylamino)ethyl)-4-methoxy-1-methyl-1H-indol-7-yl)acrylatehydrochloride (25-2) Step 1: (E)-Methyl3-(3-(2-(dimethylamino)ethyl)-4-methoxy-1-methyl-1H-indol-7-yl)acrylatehydrochloride (25-2)

In a seal tube, a mixture of 6-5 (311 mg, 1.0 mmol), methyl acrylate(0.90 mL, 10 mmol), Pd₂(dba)₃ (46 mg, 0.05 mmol), P(t-Bu)₃ (50 μL, 0.2mmol) and Cs₂CO₃ (652 mg, 2.0 mmol) in 15 mL dioxane was heated at 100OC overnight. Since MS showed incomplete reaction, methyl acrylate (0.90mL), Pd₂(dba)₃ (125 mg), P^(t)Bu₃ (2.0 mL) was added and the mixture washeated for another 6 h. After cooling to room temperature, the reactionmixture was filtered, and the filtrate was concentrated. The brown oilwas purified by flash column chromatography, eluting with CH₂Cl₂/NH₄OH(1%) to afford 25-2 as yellow solid (303 mg, 87%). The final productshowed 10% cis isomer by ¹H NMR and 34% cis isomer by HPLC.

¹H NMR (CDCl₃, 300 MHz) δ (ppm) 8.47 (d, J=15.4 Hz, 1H), 7.35 (d, J=8.2Hz, 1H), 6.68 (s, 1H), 6.48 (d, J=8.2 Hz, 1H), 6.27 (d, J=15.4 Hz, 1H),3.95 (s, 3H), 3.92 (s, 3H), 3.80 (s, 3H), 2.97-3.03 (m, 2H), 2.53-2.59(m, 2H), 2.32 (s, 6H). LRMS: Calc 316.2. found 317.2 [MH]⁺.

Example 843-(3-(2-(Dimethylamino)ethyl)-4-methoxy-1-methyl-1H-indol-7-yl)propan-1-olhydrochloride (25-4) Step 1: Methyl3-(3-(2-(dimethylamino)ethyl)-4-methoxy-1-methyl-1H-indol-7-yl)propanoate(25-3)

A mixture of 25-2 (78.6 mg, 0.25 mmol) and Pd/C (5%, 50 mg) in MeOH waspurged with nitrogen and hydrogen, and then the reaction was stirred atroom temperature. After 6 h, the reaction mixture was filtered andconcentrated to give the compound 25-3 as a pale yellow semi-solid (67mg), which was used for the next step without purification. ¹H NMR(CDCl, 300 MHz) δ (ppm) 6.82 (d, J=8.0 Hz, 1H), 6.64 (s, 1H), 6.37 (d,J=8.0 Hz, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.28-3.34 (m, 2H), 2.99-3.05(m, 2H), 2.57-2.69 (m, 4H), 2.35 (s, 6H).

Step 2:3-(3-(2-(Dimethylamino)ethyl)-4-methoxy-1-methyl-1H-indol-7-yl)propan-1-olhydrochloride (25-4)

To a suspension of 25-3 in 10 mL THF, a solution of LiAlH₄ (1.0 M inTHF, 1.1 mL) was added and the mixture was stirred at room temperaturefor 5 h. The reaction was quenched by water and extracted by EtOAc (2×50mL), and the combined organic phase was washed by brine and dried overNa₂SO₄. After concentration, the brown oil was purified by flash columnchromatography, eluting with CH₂Cl₂/5% NH₄OH/2% MeOH to afford 25-4 as acolorless oil (44 mg), and then it was converted to the HCl salt to givethe product as a white solid, mp 182-185° C. ¹H NMR (DMSO-d₆ 300 MHz) δ(ppm): 9.84 (bs, 1H), 6.98 (s, 1H), 6.78 (d, J=8.0 Hz, 1H), 6.42 (d,J=8.0 Hz, 1H), 4.54 (t, J=5.0 Hz, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 3.47(q, J=6.0 Hz, 2H), 3.17-3.25 (m, 2H), 3.06-3.14 (m, 2H), 2.96 (t, J=9.0Hz, 2H), 1.66-1.74 (m, 2H). LRMS: Calc 290.2. found 291.2 [MH]⁺.

Example 85-1N-Benzyl-2-(4-(benzyloxy)-1-ethyl-6-fluoro-1H-indol-3-yl)ethanamine(26-7) Step 1: Methyl2-(4-(benzyloxy)-6-fluoro-1H-indol-3-yl)-2-oxoacetate (26-1)

To a solution of compound 1-5b (559 mg, 2.32 mmol) in 70 mL ether,oxalyl chloride was added slowly at 0° C. After 10 min, the reactionmixture was warmed to room temperature and stirred for 6 h. After themixture was cooled to 0 OC, Et₃N (3.0 mL) and MeOH (3.0 mL) wereintroduced and the resulting mixture was stirred overnight. The reactionmixture was diluted with water and extracted with EtOAc 2×100 mL, thecombined organic phase was washed by brine and dried over Na₂SO₄. Afterconcentration, the crude product 26-1 was obtained as a brown oil (897mg), which was used in the next step without purification. ¹H NMR(CDCl₃, 300 MHz) δ (ppm): 9.09 (bs, 1H), 8.00 (d, J=3.0 Hz, 1H), 7.50(d, J=7.1 Hz, 2H), 7.28-7.41 (m, 3H), 6.72 (dd, J=1.9, 8.3 Hz, 1H), 6.51(dd, J=1.9, 11.7 Hz, 1H), 5.20 (s, 2H), 3.67 (s, 3H).

Step 2: 2-(4-(Benzyloxy)-6-fluoro-1H-indol-3-yl)ethanol (26-2)

A crude of 26-1 (2.32 mmol) and LiAlH₄ (1.32 g, 34.8 mmol) in 100 mLdioxane was heated at reflux for 2 h. The reaction mixture was cooled to0 OC and quenched by water, 15% NaOH and then water. The resultingsuspension was stirred for 30 min, and then filtered. After dried overNa₂SO₄, the organic phase was concentrated to give a brown oil, whichwas purified by flash column chromatography, eluting with hexanes/EtOAc(8:1 to 1:1) to afford 26-2 as a white solid (259 mg, 39%). ¹H NMR(CDCl₃) δ (ppm): 7.98 (bs, 1H), 7.35-7.48 (m, 5H), 6.91 (d, J=2.5 Hz,1H), 6.68 (dd, J1=1.9 Hz, J2=9.2 Hz, 1H), 6.39 (dd, J1=1.9 Hz, J2=11.5Hz, 1H), 5.14 (s, 2H), 6.81 (q, J=6.3 Hz, 2H), 3.07 (t, J=6.3 Hz, 2H),1.47 (t, J=6.0 Hz, 1H).

Step 3, 4 and 5: 2-(4-(Benzyloxy)-1-ethyl-6-fluoro-1H-indol-3-yl)ethanol(26-5)

To a solution of 26-2 (259 mg, 0.91 mmol) and imidazole (494 mg, 7.26mmol) in 25 mL DMF, TBDMSCl (547 mg, 3.63 mmol) was added and thereaction mixture was stirred at room temperature overnight. The reactionmixture was partitioned with EtOAc and brine, and the combined organicphase was washed by brine and dried over Na₂SO₄. After concentration,the product 26-3 was obtained as brown oil, which was used for the nextstep without purification.

The crude 26-3 was dissolved in 50 mL DMF and the mixture was cooled to0 OC. NaH (730 mg, 18.2 mmol) was added at once and stirred at thistemperature for 20 min. Then MeI (1.46 mL, 18.2 mmol) was added andstirred for 2 h. The reaction mixture was quenched by water, andextracted with EtOAc 2×150 mL. The combined organic phase was washed bybrine and dried over Na₂SO₄. After concentration, the product 26-4 wasobtained as brown liquid, and it was used in the next step withoutpurification.

To a solution of the crude 26-4 in 15 mL THF, TBAF solution (1.0 M inTHF, 5.5 mL) was introduced via syringe and the mixture was stirred for2 h. After diluted with EtOAc, the mixture was washed with water, brine,and dried over Na₂SO₄, then concentrated in vacuo to give a brown oil,which was purified by flash column chromatography, eluting withhexanes/EtOAc (8:1 to 1:1) to afford the product 26-5 as a pale yellowoil (259 mg, 91%). ¹H NMR (CDCl₃) δ (ppm): 7.34-7.48 (m, 5H), 6.82 (s,1H), 6.62 (dd, J=2.2, 9.6 Hz, 1H), 6.37 (dd, J=1.9, 11.5 Hz, 1H), 5.14(s, 2H), 4.01 (q, J=7.4 Hz, 2H), 3.79 (q, J=6.3 Hz, 2H), 3.05 (t, J=6.3Hz, 2H), 1.48 (t, J=6.0 Hz, 1H), 1.41 (t, J=7.4 Hz, 3H).

Step 6 and 7:N-Benzyl-2-(4-(benzyloxy)-1-ethyl-6-fluoro-1H-indol-3-yl)ethanamine_(26-7)

To a solution of 26-5 (60 mg, 0.19 mmol) and Et₃N (0.16 mL, 1.15 mmol)in 12 mL CH₂Cl₂, MsCl (23 μL, 0.29 mmol) was added dropwise and thereaction mixture was stirred for 2 h. The reaction mixture was dilutedwith CH₂Cl₂ and washed with brine. The organic phase was dried overNa₂SO₄ and concentrated to get 26-6 as a colorless oil.

Crude 26-6 was dissolved in 5 mL THF and transferred to a sealed tube.BnNH₂ solution (2.1 mL, 19 mmol), NaI (10 mg), Na₂CO₃ (201 mg, 1.9 mmol)were added. The tube was sealed and heated at 80 OC overnight. Aftercooling to room temperature, the reaction mixture was partitioned withEtOAc and water, and the organic phase was washed with brine and driedover Na₂SO₄. After concentration, the brown oil was purified by flashcolumn chromatography, eluting with CH₂Cl₂/MeOH/NH₄OH to afford 26-7 asa yellow oil which was converted into the HCl salt to give a yellowsolid, mp 167-171° C. H NMR (DMSO-d₆, 300 MHz) δ (ppm): 9.04 (bs, 1H),7.30-7.51 (m, 10H), 7.12 (s, 1H), 6.93 (dd, J=1.9, 9.9 Hz, 1H), 6.53(dd, J=1.9, 12.0 Hz, 1H), 5.21 (s, 2H), 4.04 (q, J=7.4 Hz, 2H),5.95-4.00 (m, 2H), 3.14 (bs, 4H), 1.29 (t, J=7.4 Hz, 3H). LRMS: Calc402.2. found 403.2 [MH]⁺.

Example 85-2 3-(2-(benzylamino)ethyl)-1-ethyl-6-fluoro-1H-indol-4-ol(26-8) Step 7: 3-(2-(benzylamino)ethyl)-1-ethyl-6-fluoro-1H-indol-4-ol(26-8)

Following the procedure (step 2-1, scheme 23) used to prepare compound23-2, compound 26-7 gave compound 26-8 in 37% yield (67.5 mg) asoff-white solid. ¹H NMR (300 MHz, MeOD-d6) δ (ppm): 7.41 (d, J=20.1 Hz,5H), 6.96 (s, 1H), 6.59 (dd, J=9.9, 2.1 Hz, 1H), 6.19 (dd, J=11.2, 2.0Hz, 1H), 4.20 (s, 2H), 4.05 (q, J=7.3 Hz, 2H), 3.37 (dd, J=13.4, 6.1 Hz,2H), 3.26-3.16 (m, 2H), 1.37 (t, J=7.2 Hz, 3H). LRMS: calc 312.16. found313.1 [MH]+.

The compound in Table 27 was made according to processes described inScheme 26.

TABLE 27 Ex. ID Procedure Structure name number number NMR MS of scheme

2-(4- (benzyl- oxy)-1- ethyl-6- fluoro-1H- indol-3- yl)-N- phenethyl-ethanamine 85-3 26-9 ¹H NMR δ (ppm): (300 MHz, MeOD-d6) δ (ppm):7.52-7.43 (m, 2H), 7.41- 7.28 (m, 3H), 7.22-7.11 (m, 3H), 7.08-7.00 (m,2H), 6.73 (s, 1H), 6.67 (dd, J = 9.8, 2.0 Hz, 1H), 6.41 (dd, J = 11.8,1.9 Hz, 1H), 5.12 (s, 2H), 3.99 (q, J = 7.2 Hz, 2H), 2.93 (t, J = 6.9Hz, 2H), 2.80 (t, J = 6.7 Hz, 2H), 2.67 (dt, J = 5.3, 4.3 Hz, 4H), 1.31(t, J = 7.2 Hz, 3H) calc 416.23, found 417.3 [MH]+ 26 Step 1-6

1-ethyl-6- fluoro-3- (2-(3- (trifluoro- methyl) phenethyl- amino)ethyl)-1H- indol-4- ol 85-4 26-10 ¹H NMR (300 MHz, MeOD-d6) δ (ppm):7.56- 7.28 (m, 4H), 6.77 (s, 1H), 6.49 (dd, J = 10.0, 2.1 Hz, 1H), 6.15(dd, J = 11.6, 2.1 Hz, 1H), 3.98 (q, J = 7.2 Hz, 2H), 2.97 (dt, J = 9.7,4.8 Hz, 4H), 2.86 (s, 4H), 1.32 (t, J = 7.2 Hz, 3H) calc 394.17, found395.1 [MH]+ 26

1-ethyl-6- fluoro-3- (2- (phenethyl- amino) ethyl)-1H- indol-4- ol 85-526-1 ¹H NMR (300 MHz, MeOD-d6) δ (ppm): 7.15 (40, J = 19.7, 10.9, 4.9Hz, 5H), 6.74 (s, 1H), 6.48 (dd, J = 10.0, 2.1 Hz, 1H), 6.14 (dd, J =11.6, 2.1 Hz, 1H), 3.97 (q, J = 7.2 Hz, 2H), 2.97 (dt, J = 9.3, 4.6 Hz,4H), 2.82 (td, J = 11.5, 6.9 Hz, 4H), 1.32 (t, J = 7.2 Hz, 3H) calc326.18, found 327.2 [MH]+ 26

Example 86 Synthesis of3-(3-(2-(dimethylamino)ethyl)-7-fluoro-4-methoxy-1-ethyl-1H-indol-5-yl)propan-1-ol(27-3) Step 1: (E)-methyl3-(7-fluoro-4-methoxy-1l-ethyl-3-(2-(methylamino)-2-oxoethyl)-1H-indol-5-yl)acrylate (27-1)

To a solution of 27-0 (7.5 g, 21.0 mmol) (prepared as 8-11 scheme 8) inanhydrous Et₃N (20 mL) was added Pd(OAc)₂ (471 mg, 2.1 mmol), PPh₃ (1100mg, 4.2 mmol) and methyl acrylate (2.7 g, 31.3 mmol). The mixture wasrefluxed for 24 h. After cooled to room temperature, the mixture wasfiltered, and the residue was evaporated to obtain 27-1 (7.5 g, 20.7mmol) as red oil, which was used in the next step without furtherpurification. LRMS: calc 362.1 and found 363.1 [MH]⁺.

Step 2: methyl3-(3-(2-(dimethylamino)-2-oxoethyl)-7-fluoro-4-methoxy-1-ethyl-1H-indol-5-yl)propanoate(27-2)

To a solution of 27-1 (200 mg, 0.57 mmol) in 20 mL of MeOH was added 0.1g of Pd/C (10%). The mixture was stirred over night under H₂ atmosphereat room temperature. The mixture was filtered and the filtrate was toafford 27-2 (150 mg, 0.42 mmol, 74%) as a white solid. LRMS: calc 364.1and found: 365.1 [MH]⁺.

Step 3:3-(3-(2-(dimethylamino)ethyl)-7-fluoro-4-methoxy-1-ethyl-1H-indol-5-yl)propan-1-ol(27-3)

To a solution of 27-2 (150 mg, 0.42 mmol) in anhydrous THF (20 mL) wasadded LiAlH₄ (78 mg, 2.05 mmol) and the mixture was stirred at roomtemperature for two hours. Na₂SO₄.10H₂O was added, the solid wasfiltered off and washed with ethylacetate (20 mL). The filtrate wasconcentrated in under vacuum. The resulting residue was purified bycolumn chromatography on (DCM:MeOH=50:1) to afford compound 27-3 (30 mg,23%) as a white solid. ¹H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.02 (s, 1H),6.65 (d, J=13.2 Hz, 1H), 4.16 (q, J=6.8 Hz, 2H), 3.72 (s, 3H), 3.51 (t,J=6.6 Hz, 2H), 3.22-3.17 (m, 2H), 3.10-3.03 (m, 2H), 2.74 (s, 6H),2.72-2.64 (m, 2H), 1.79-1.72 (m, 2H), 1.30 (t, J=7.2 Hz, 3H). LRMS: calc322.4 and found: 323.0 [MH]⁺.

Example 873-(3-(2-(dimethylamino)ethyl)-1-ethyl-7-fluoro-4-methoxy-1H-indol-5-yl)propan-1-amine(28-4) Step 1:3-(3-(2-(dimethylamino)-2-oxoethyl)-1-ethyl-7-fluoro-4-methoxy-1H-indol-5-yl)propanoic acid (28-2)

To a solution of 28-1 (200 mg, 0.55 mmol) (prepared using similarsynthetic scheme as 27-2) in MeOH (4 mL) was added 2N NaOH (4 mL), andthen the mixture was stirred at room temperature for one hour. Thereaction mixture was neutralized with 1N HCl to pH=7, then extractedwith ethyl acetate (3×100 mL). The organic layer was concentrated undervacuum to afford 28-2 (180 mg, 94%) as a yellow solid. LRMS: calc 350.2and found: 351.1 [MH]⁺.

Step 2:3-(3-(2-(dimethylamino)-2-oxoethyl)-1-ethyl-7-fluoro-4-methoxy-1H-indol-5-yl)propanamide(28-3)

A mixture of 28-2 (180 mg, 0.51 mmol), HATU (388 mg, 1.02 mmol), DIPEA(220 mg, 1.7 mmol) and ammonium chloride (73 mg, 1.36 mmol) in THF (10mL) was stirred at room temperature overnight. Water (10 mL) was added,and the reaction mixture was extracted with ethyl acetate (3×20 mL). Thecombined organic phase was dried over MgSO₄, filtered and evaporated togive crude product, which was purified by preparative TLC (petroleumether/ethyl acetate=1:1) to afford 28-3 (150 mg, 84%) as a yellow solid.LRMS: calc 349.2 and found: 350.0 [M+1].

Step 3:3-(3-(2-(dimethylamino)ethyl)-1-ethyl-7-fluoro-4-methoxy-1H-indol-5-yl)propan-1-amine(28-4)

To a solution of 28-3 (100 mg, 0.28 mmol) in THF (10 mL) was addedlithium aluminum hydride (44 mg, 1.15 mmol) in portions. The mixture wasstirred at room temperature overnight. NaSO₄.10H₂O was added, then themixture was filtered and the filtrate was evaporated. The crude productwas purified by preparative HPLC (acid conditions) to afford 28-4 (10mg, 11%) as a yellow solid. ¹H-NMR (400 MHz, CDCl₃): δ (ppm) 6.83 (s,1H), 6.66 (d, J=6.6 Hz, 1H), 4.21 (q, J=7.2 Hz, 2H), 3.80 (s, 3H), 3.04(t, J=7.2 Hz, 2H), 2.77-2.69 (m, 6H), 2.62-2.60 (br.s, 2H), 2.40 (s,6H), 1.85-1.78 (m, 2H), 1.42 (t, J=6.8 Hz, 3H). LRMS: calc 321.4 andfound: 322.0 [M+1].

Example 882-(5-(2-(1H-benzo[d]imidazol-2-yl)ethyl)-1-ethyl-7-fluoro-4-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine(29-4) Step 1:N-(2-aminophenyl)-3-(3-(2-(dimethylamino)-2-oxoethyl)-1-ethyl-7-fluoro-4-methoxy-1H-indol-5-yl)propanamide(29-2)

A mixture of 28-1 (300 mg, 0.86 mmol), HATU (490 mg, 1.29 mmol), DIPEA(278 mg, 2.15 mmol) and benzene-1,2-diamine (140 mg, 1.29 mmol) in THF(10 mL) was stirred at room temperature overnight. Water (10 mL) wasadded, and the reaction mixture was extracted with ethyl acetate (3×20mL). The combined organic phase was dried over MgSO₄, filtered andevaporated to give crude product, which was purified by preparative TLC(petroleum ether/ethyl acetate=1:1) to afford 29-2 (250 mg, 66%) as alight yellow solid. LRMS: calc 440.2 and found: 441.2 [M+1].

Step 2:2-(5-(2-(1H-benzo[d]imidazol-2-yl)ethyl)-1-ethyl-7-fluoro-4-methoxy-1H-indol-3-yl)-N,N-dimethylacetamide(29-3)

A solution of 29-2 (230 mg, 0.52 mmol) in acetic acid (10 mL) was heatedto 80° C. for 3 h. After cooled to room temperature, water (10 mL) andsat. aqeuous NaHCO₃ (30 mL) were added. The mixture was extracted withethyl acetate (3×20 mL). The combined organic layer was dried withMgSO₄, filtered and evaporated to afford 29-3 (150 mg, 68%) as yellowoil. LRMS: calc 422.5 and found: 423.2 [M+1].

Step 3:2-(5-(2-(1H-benzo[d]imidazol-2-yl)ethyl)-1-ethyl-7-fluoro-4-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine(29-4)

To a solution of 29-3 (100 mg, 0.24 mmol) in THF (10 mL) was addedlithium aluminum hydride (19 mg, 0.48 mmol). The mixture was stirred atroom temperature overnight. Na₂SO₄.10H₂O was added and the reactionmixture was filtered and the filtrate was evaporated to give the crudeproduct which was purified by preparative HPLC (basic condition,water/CH₃CN, 43-53% CH₃CN in 7.5 min, RT=7.3 min) to afford 29-4 (22 mg,23%) as a yellow solid. ¹H-NMR (400 MHz, CDCl₃): δ (ppm) 7.52-7.50(br.s, 2H), 7.20-7.16 (m, 2H), 6.76 (s, 1H), 6.66 (d, J=12.8 Hz, 1H),3.96 (q, J=7.2 Hz, 2H), 3.81 (s, 3H), 3.14 (t, J=7.2 Hz, 2H), 3.06-2.98(m, 4H), 2.69 (t, J=7.6 Hz, 2H), 2.38 (s, 6H) 1.30 (t, J=7.2 Hz, 3H).LRMS: calc 408.5 and found: 409.2 [M+1].

Example 89N-benzyl-2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)ethanamine (30-15)Step 1: 2-bromo-4-chloro-6-fluorophenol (30-2)

To a solution of 30-1 (29.31 g, 200 mmol) in acetic anhydride (200 mL)was added bromine (32 g, 200 mmol) dropwise. After the addition, themixture was stirred at room temperature overnight and then was pouredinto ice water. 100 mL of saturated aqueous NaHSO₃ aqueous was added.The precipitate was filtered and dried over Na₂SO₄ to afford 30-2 (48.1g) as a white solid. LRMS: calc 223.9 and found: 224.9 [M+1].

Step 2: 1-bromo-5-chloro-2-ethoxy-3-fluorobenzene (30-3)

To a mixture of 30-2 (48.1 g, 214 mmol) and Na₂CO₃ (34 g, 321 mmol) inacetone (300 mL) was added a solution of Et₂SO₄ (39.6 g, 257 mmol) inacetone (100 mL) dropwise over 20 minutes and then the mixture wasstirred at room temperature for one hour. The solid was filtered off andthe filtrate was concentrated under vacuum to afford 30-3 (48.6 g, 90%)as a white solid. LRMS: calc 251.9 and found: 252.9 [M+1].

Step 3: 3-bromo-1-chloro-4-ethoxy-5-fluoro-2-nitrobenzene (30-4)

To a solution of 30-3 (48.6 g, 192 mmol) in concentrated H₂SO₄ (240 mL)stirred at room temperature was added HNO₃ (19 mL) dropwise. The mixturewas allowed to stir at room temperature for two hours. The reactionmixture was then poured into ice water and extracted with ethyl acetate(3×800 mL). The organic layer was combined and concentrated under vacuumto get a crude product which was purified on silica gel columnchromatography eluting with petroleum ether/ethyl acetate (10:1 to 1:1)to afford 30-4 (22.9 g, 40%) as a yellow solid. LRMS: calc 296.9 andfound: 297.9 [M+1].

Step 4: 2-bromo-6-chloro-3-ethoxy-4-fluorobenzenamine (30-5)

To a solution of 30-4 (22.9 g, 77 mmol) in ethanol (100 mL) at roomtemperature was added concentrated HCl (74 mL) and SnCl₂ (44 g, 231mmol). The mixture was allowed to stir at room temperature for 4 hours.The reaction mixture was poured into water and extracted with ethylacetate (3×150 mL), the organic layer was combined and was concentratedunder vacuum to get a crude product which was purified on silica gelcolumn chromatography eluting with petroleum ether/ethyl acetate (5:1 to1:1) to afford 30-5 (16 g, 78%) as a white solid. LRMS: calc 266.9 andfound: 267.9 [M+1].

Step 5: N-(2-bromo-6-chloro-3-ethoxy-4-fluorophenyl)acetamide (30-6)

A solution of 30-5 (16 g, 59.7 mmol) in acetic anhydride (50 mL) wasstirred at room temperature for one hour. The precipitate was filteredand washed with ether to afford 30-6 (14 g, 76%) as a white solid. LRMS:calc 308.9 and found: 309.9 [M+1].

Step 6: (Z)-methyl 4-(N-(2-bromo-6-chloro-3-ethoxy-4-fluorophenyl)acetamido) but-2-enoate (30-7)

To a solution of 30-6 (12.42 g, 40 mmol) in THF (100 mL) was added NaH(1.92 g, 80 mmol) in portions, the mixture was stirred at roomtemperature for 30 min before (E)-methyl 4-bromobut-2-enoate (8.6 g, 48mmol) was added. The mixture was stirred overnight. Water (150 mL) wasadded to the reaction mixture and extracted with ethyl acetate (3×200mL). The combined organic layers were concentrated under vacuum toobtain a yellow residue, which was purified on silica gel columnchromatography eluting with petroleum ether/ethyl acetate (5:1 to 1:1)to afford 30-7 (11.8 g, 72%) as a white solid. LRMS: calc 407.0 andfound: 408.0 [M+1].

Step 7: methyl 2-(7-chloro-4-ethoxy-5-fluoro-1H-indol-3-yl)acetate(30-8a) and methyl2-(1-acetyl-7-chloro-4-ethoxy-5-fluoro-1H-indol-3-yl)acetate (30-8b)

To a solution of 30-7 (11.8 g, 28.9 mmol) in anhydrous DMF (250 mL) wasadded Pd(OAc)₂ (0.64 g, 2.87 mmol), Bu₄NBr (18.36 g, 57.4 mmol) andDIPEA (5.8 g, 57.4 mmol) under N₂. The mixture was stirred at 80° C. forthree hours before it was cooled to room temperature. Then the reactionmixture was poured into ice water and extracted with ethyl acetate(3×150 mL). The combined organic layer was concentrated to get a crudeproduct which was purified on silica gel column chromatography elutingwith petroleum ether/ethyl acetate (10:1 to 51:1) to afford a mixture30-8a and 30-8b (6 g) as light yellow oil. LRMS (8-30-8a): calc 285.0and found: 286.0 [M+1]. LRMS (30-8b): calc 327.07 and found: 328.0[M+1].

Step 8: 2-(7-chloro-4-ethoxy-5-fluoro-1H-indol-3-yl)acetic acid (30-9)

To a solution of mixture 30-8a and 30-8b (500 mg, 1.53 mmol) in water(50 mL) was added 2N NaOH (8 mL), then the mixture was stirred at roomtemperature for one hour. The mixture was neutralized with HCl to pH=7,then extracted with ethyl acetate (3×100 mL). The combined organic layerwas concentrated under vacuum to afford 30-9 (582 mg) as a yellow solid.LRMS: calc 271.0 and found: 272.1 [M+1].

Step 9: methyl 2-(7-chloro-4-ethoxy-5-fluoro-1H-indol-3-yl)acetate(30-10)

To a solution of 30-9 (582 mg, 6.4 mmol) in CH₃OH (20 mL) was addedSOCl₂ (1 mL). The mixture was refluxed for 2 h before it was cooled toroom temperature, the solvent was removed under reduce pressure. Theresulting residue was partitioned between water (30 mL) and ethylacetate (30 mL). The organic layer was separated and the aqueous layerwas extracted with ethyl acetate (3×20 mL). The combined organic layerswere combined, washed with brine (3×20 mL), dried over Na₂SO₄, filteredand concentrated to afford 30-10 (500 mg, 82%) as a light yellow solid.LRMS: calc 285.0 and found: 286.1 [M+1].

Step 10: methyl2-(7-chloro-4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)acetate (30-11)

To a solution of 30-10 (2 g, 7 mmol) in acetone (40 mL) was added K₂CO₃(3 g, 21 mmol) and MeI (1.2 g, 8.4 mmol). The reaction mixture wasrefluxed overnight before it was cooled to room temperature. The solidwas filtered off and the filtrate was evaporated to give the crudeproduct, which was purified on silica gel column chromatography elutingwith hexane/ethyl acetate (1:5) to afford 30-11 (1.4 g, 67%) as a yellowsolid. LRMS: calc 299.1 and found: 300.1 [M+1].

Step 11: methyl 2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)acetate(30-12)

A mixture of 30-11 (1.4 g, 4.7 mmol), Pd/C (280 mg, 20%) and Et₃N (1.42g, 14.1 mmol) in MeOH (20 mL) was stirred under hydrogen atmosphere atroom temperature overnight. The mixture was filtered and the filtratewas concentrated to afford 30-12 (1 g, 92%) as a yellow solid. LRMS:calc 265.1 and found: 266.1 [M+1].

Step 12: 2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)acetic acid (30-13)

To a solution of 30-12 (45 mg, 0.17 mmol) in MeOH (10 mL) was added 2NNaOH (8 mL). The mixture was refluxed for one hour. After cooled to roomtemperature, the mixture was neutralized with hydrochloric acid to pH=7,extracted with ethyl acetate (3×100 mL). The combined organic layer waswashed with brine (30 mL), dried over MgSO₄ and concentrated to afford30-13 (40 mg, 94%) as a yellow solid. LRMS: calc 251.1 and found: 252.0[M+1].

Step 13: N-benzyl-2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)acetamide(30-14)

A solution of 30-13 (30 mg, 0.12 mmol), HATU (76 mg, 0.2 mmol), DIPEA(39 mg, 0.3 mmol) and phenylmethanamine (17 mg, 0.16 mmol) in THF (5 mL)was stirred at room temperature overnight. Water (5 mL) and ethy acetate(10 mL) were added to the mixture. The organic layer was separated,washed with brine (3×20 mL), dried over MgSO4, filtered and evaporatedto give a crude product, which was purified by preparative TLC(petroleum ether/ethyl acetate=1:1) to afford 30-14 (28 mg, 69%) as alight yellow solid. LRMS: calc 340.2 and found: 341.1 [M+1].

Step 14: N-benzyl-2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)ethanamine(30-15)

To a solution of LiAlH₄ (5 mg, 0.12 mmol) and AlCl₃ (16 mg, 0.12 mmol)in THF (5 mL) was added a solution of 30-14 (14 mg, 0.04 mmol) in THF (5mL) dropwise, the mixture was stirred at room temperature overnightbefore Na₂SO₄.10H₂O was added. The mixture was filtered and the filtratewas evaporated to give a crude product which was purified by preparativeHPLC (acid condition, water/CH₃CN, 25-30% CH₃CN in 7.5 min, RT=6.5 min)to afford 30-15 (8 mg, 61%) as a yellow solid. ¹H-NMR (400 MHz, CDCl₃):δ (ppm) 7.30-7.28 (m, 5H), 7.00-6.95 (m, 1H), 6.87-6.84 (m, 2H), 4.24(q, J=7.2 Hz, 2H), 4.01-3.98 (br.s, 2H), 3.67 (s, 3H), 3.27-3.22 (br.s,2H), 3.15-3.11 (br.s, 2H), 1.34 (t, J=6.8 Hz, 3H). LRMS: calc 326.2 andfound: 327.0 [M+1].

The compounds in Table 28 were made according to processes described inScheme 30.

TABLE 28 Ex. ID Procedure Structure name number number NMR MS of scheme

N-benzyl-2- (4-ethoxy-5- fluoro-1- methyl-1H- indol-3- yl)ethanamine 8930-15 ¹H-NMR (400 MHz, CDCl₃): δ (ppm) 7.30-7.28 (m, 5H), 7.00-6.95 (m,1H), 6.87-6.84 (m, 2H), 4.24 (q, 2H), 4.01-3.98 (br.s, 2H), 3.67 (s,3H), 3.27-3.22 (br.s, 2H), 3.15-3.11 (br.s, 2H), 1.34 (t, J = 6.8 Hz,3H). calc 326.2, found 327.0 [MH]+ 30

N-(2-(4- ethoxy-5- fluoro-1- methyl-1H- indol-3- yl)ethyl)-2,3-dihydro-1H- inden-2- amine 90 30-16 ¹H-NMR (400 MHz, CDCl₃): δ (ppm)7.16-7.11 (m, 4H), 6.99-6.94 (m, 1H), 6.86 (d, J = 3.2 Hz, 1H), 6.84 (s,1H), 4.29 (q, 2H), 3.72-3.68 (m, 1H), 3.67 (s, 3H), 3.21-3.15 (m, 2H),3.07 (s, 3H), 3.09-3.06 (m, 1H), 2.85-2.79 (m, 2H), 1.43 (t, J = 6.8 Hz,3H). calc 352.2, found 353.2 [MH]+ 30

N-(2- chlorobenzyl)- 2-(4- ethoxy-5- fluoro-1- methyl-1H- indol-3-yl)ethanamine 91 30-17 ¹H-NMR (400 MHz, CDCl₃): δ (ppm) 7.39-7.37 (m,1H), 7.34-7.32 (m, 1H), 7.22-7.19 (m, 2H), 6.97- 6.94 (m, 1H), 6.87-6.83(m, 2H), 4.26 (q, 2H), 3.94 (s, 2H), 3.69 (s, 3H), 3.09 (t, J = 6.4 Hz,2H), 3.01(t, J = 6.4 Hz, 2H), 1.43 (d, J = 7.2 Hz, 3H). calc 360.8,found 361.0, 362.9 [MH]+ 30

N- (benzo[d] [1,3]dioxol-5- ylmethyl)-2- (4-ethoxy-5- fluoro-1-methyl-1H- indol-3- yl)ethanamine 92 30-18 ¹H-NMR (400 MHz, CDCl₃): δ(ppm) 7.00-6.95 (m, 1H), 6.88-6.85 (m, 3H), 6.77-6.72 (m, 2H), 5.93 (s,2H), 4.28 (q, 2H), 3.79 (s, 2H), 3.70 (s, 3H), 3.12 (t, J = 6.0 Hz, 2H),3.06 (t, J = 6.0 Hz, 2H), 1.43 (t, J = 7.0 Hz, 3H). calc 326.2, found327.0 [MH]+ 30

N-(2-(4- ethoxy-5- fluoro-1- methyl-1H- indol-3- yl)ethyl)-2,3-dihydro-1H- inden-1- amine 93 30-19 ¹H-NMR (400 MHz, MeOD-d6): δ (ppm)7.50 (d, J = 7.6 Hz, 1H), 7.42-7.38 (m, 2H), 7.32-7.28 (m, 1H), 7.08 (s,1H), 7.05-6.97 (m, 2H), 4.98-4.84 (m, 1H), 4.25 (q, 2H), 3.75 (s, 3H),3.50-3.37 (m, 2H), 3.28- 3.16 (m, 3H), 3.05-2.97 (m, 1H), 2.64-2.55 (m,1H), 2.27-2.21 (m, 1H), 1.37 (t, J = 7.0 Hz, 3H). calc 352.4, found353.0 [MH]+ 30

2-(4-ethoxy- 5-fluoro-1- methyl-1H- indol-3-yl)- N-(3- methylbenzyl)ethanamine 94 30-20 ¹H-NMR (400 MHz, CDCl₃): δ (ppm) 7.19 (t, J = 7.2Hz, 1H), 7.11-7.04 (m, 3H), 6.98-6.93 (m, 1H), 6.85 (dd, J = 8.8, 3.2Hz, 1H), 6.81 (s, 1H), 4.25 (q, 2H), 3.80 (s, 2H), 3.68 (s, 3H), 3.08(t, J = 7.2 Hz, 2H), 2.99 (t, J = 6.8 Hz, 2H), 2.32 (s, 3H), 1.41 (t, J= 7.2 Hz, 3H). calc 340.4, found 341.0 [MH]+ 30

2-(4-ethoxy- 5-fluoro-1- methyl-1H- indol-3-yl)- N-(2- (trifluoro-methyl) benzyl) ethanamine 95 30-21 ¹H-NMR (400 MHz, CDCl₃): δ (ppm)7.63-7.59 (m, 2H), 7.52-7.41 (m, 2H), 6.99-6.84 (m, 3H), 4.27 (s, 2H),4.21 (q, 2H), 3.66 (s, 3H), 3.41 (t, J = 6.0 Hz, 2H), 3.18 (t, J = 6.4Hz, 2H), 1.32 (t, J = 1.2 Hz, 3H). calc 394.2, found 394.9 [MH]+ 30

2-(4-ethoxy- 5-fluoro-1- methyl-1H- indol-3-yl)- N-(2- (trifluoro-methyl) benzyl) ethanamine 96 30-22 ¹H-NMR (400 MHz, CDCl₃): δ (ppm)7.59 (s, 1H), 7.51 (t, J = 6.8 Hz, 2H), 7.41 (t, J = 7.6 Hz, 1H),6.99-6.94 (m, 1H), 6.87- 6.83 (m, 2H), 4.26 (q, 2H), 3.89 (s, 2H), 3.68(s, 3H), 3.09 (t, J = 6.8 Hz, 2H), 3.01 (t, J = 6.4 Hz, 2H), 1.41 (t, J= 7.2 Hz, 3H). calc 394.4, found 395.1 [MH]+ 30

4-(2-(4- ethoxy-5- fluoro-1- methyl-1H- indol-3- yl)ethyl) morpholine 9730-23 ¹H-NMR (400 MHz, CDCl₃): δ (ppm) 7.06-6.96 (m, 1H), 6.92 (s, 1H),6.88 (dd, J = 9.2, 3.6 Hz, 1H), 4.33 (q, 2H), 4.05-3.98 (m, 4H), 3.69(s, 3H), 3.58 (d, J = 11.6 Hz, 2H), 3.33-3.30 (m, 4H), 2.88 (t, J = 9.2Hz, 2H), 1.41 (t, J = 7.0 Hz, 3H). calc 306.4, found 307.0 [MH]+ 30

(1-(2-(4- ethoxy-5- fluoro-1- methyl-1H- indol-3- yl)ethyl)pyrrolidin-2- yl)methanol 98 30-24 ¹H-NMR (400 MHz, CDCl₃): δ (ppm)7.00-6.86 (m, 3H),4.31 (q, 2H), 3.99- 3.97 (br.s, 2H), 3.78 (d, J = 4.0Hz, 1H), 3.68-3.66 (m, 4H), 3.58-3.56 (br.s, 1H), 3.36-3.26 (m, 3H),2.97 (d, J = 6.4 Hz, 1H), 2.15-2.02 (m, 3H), 1.98 (d, J = 5.6 hz, 1H),1.40 (d, J = 7.0 Hz, 3H). calc 320.2, found 321.0 [MH]+ 30

2-(4-ethoxy- 5-fluoro-1- methyl-1H- indol-3-yl)- N- phenethyl-ethanamine 99 30-25 ¹H-NMR (400 MHz, CDCl₃): δ (ppm) 7.19-7.02 (br.s,5H), 6.99-6.96 (m, 2H), 6.87-6.85 (m, 1H), 4.33 (q, 2H), 3.59 (s, 3H),3.45-3.17 (m, 8H), 1.42- 1.40 (br.s, 3H). calc 340.2, found 341.0 [MH]+30

2-(benzo [d][1,3] dioxol-5-yl)- N-(2-(4- ethoxy-5- fluoro-1- methyl-1H-indol-3- yl)ethyl) ethanamine 100 30-26 ¹H-NMR (400 MHz, CDC13): δ (ppm)6.99-6.94 (m, 1H), 6.87-6.84 (m, 2H), 6.58 (d, J = 7.6 Hz, 1H), 6.53 (s,1H), 6.47 (d, J = 8.0 Hz, 1H), 5.88 (s, 2H), 4.29 (q, 2H), 3.63 (s, 3H),3.36- 3.34 (br.s, 2H), 3.21-3.13 (m, 4H), 2.88 (t, J = 7.2 Hz, 2H), 1.38(t, J = 7.2 Hz, 3H). calc 384.2, found 385.0 [MH]+ 30

2-(4-ethoxy- 5-fluoro-1- methyl-1H- indol-3-yl)- N-(2- (pyridin-2-yl)ethyl) ethanamine 101 30-27 ¹H-NMR (400 MHz, CDCl₃): δ (ppm) 7.89 (t,J = 7.6 Hz, 1H), 7.80 (d, J = 4.4 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H),7.32 (t, J = 6.0 Hz, 1H), 7.01-6.96 (m, 2H), 6.90 (dd, J = 8.8, 3.2 Hz,1H), 4.27 (q, 2H), 3.69 (s, 3H), 3.44 (d, J = 5.6 Hz, 4H), 3.33-3.30 (m,2H), 3.21 (t, J = 6.0 Hz, 2H), 1.38 (t, J = 6.8 Hz, 3H). calc 341.2,found 342.1 [MH]+ 30

2-(4-ethoxy- 5-fluoro-1- methyl-1H- indol-3-yl)- N-(thiophen- 2-ylmethyl) ethanamine 102 30-28 ¹H-NMR (400 MHz, CDCl₃): δ (ppm)7.19-7.18 (m, 1H), 6.95-6.80 (m, 5H), 4.25 (q, 2H), 4.01 (s, 2H), 3.67(s, 3H), 3.05-2.99 (m, 4H), 1.41 (t, J = 7.0 Hz, 3H). calc 332.1, found333.1 [MH]+ 30

4-ethoxy-5- fluoro-1- methyl-3-(2- (pyrrolidin-1- yl)ethyl)-1H- indole103 30-29 ¹H-NMR (400 MHz, CDCl₃): δ (ppm) 7.01-6.87 (m, 3H), 4.32 (q,2H), 3.83- 3.81 (m, 2H), 3.69 (s, 3H), 3.40-3.25 (m, 4H), 2.83- 2.79 (m,2H), 2.12-2.03 (m, 4H), 1.41 (t, J = 7.0 Hz, 3H). calc 290.1, found291.0 [MH]+ 30

Example 105 1-ethyl-6-fluoro-3-(2-(isoindolin-2-yl)ethyl)-1H-indol-4-ol(31-4) Step 1:2-(4-(benzyloxy)-1-ethyl-6-fluoro-1H-indol-3-yl)-1-(isoindolin-2-yl)ethanone (31-2)

A mixture of 31-1 (100 mg, 0.306 mmol), isoindoline (47 mg, 0.398 mmol)and HATU (232 mg, 0.611 mmol) in THF (10 mL) was stirred for 10 min atroom temperature. DIPEA (99 mg, 0.764 mmol) was added and the reactionmixture was stirred overnight. The volatiles were evaporated and theresulting residue was partitioned between ethyl acetate (10 mL) andwater (10 mL). The organic layer was separated and washed with brine(3×10 mL), dried over Na₂SO₄ and concentrated under vacuum. Theresulting residue was purified on silica gel column chromatographyeluting with dichloromethane/methanol (100:1) to afford 31-2 (180 mg,70%) as a white solid. LRMS: calc 428.2 and found: 429.1 [M+1]. Generalconditions for step 1: amine, BOP, TEA in DMF.

Example 104 Step 2:4-(benzyloxy)-1-ethyl-6-fluoro-3-(2-(isoindolin-2-yl)ethyl)-1H-indole(31-3)

To a solution of LiAlH₄ (100 mg, 2.6 mmol) in THF (30 mL) was addedaluminum trichloride (463 mg, 3.51 mmol) at 0° C. After stirring for 10min, a solution of 31-2 (180 mg, 0.42 mmol) in THF (5 mL) was addeddropwise. The reaction mixture was stirred for 5 min before Na₂SO₄.10H₂Owas added to quench the reaction. The solid was filtered off and thefiltrate was evaporated. The resulting residue was purified on silicagel column chromatography eluting with dichloromethane/methanol (10:1)to get 31-3 (100 mg, 57%) as a yellow solid. ¹H-NMR (400 MHz, CDCl₃): δ(ppm) 7.46 (d, J=7.2 Hz, 2H), 7.31-7.26 (m, 4H), 7.27 (t, J=3.6 Hz, 1H),7.09-7.06 (m, 2H), 6.93 (s, 1H), 6.65 (d, J=7.2 Hz, 1H), 6.42 (d, J=7.2Hz, 1H), 5.06 (s, 2H), 4.02-4.00 (m, 6H), 3.27 (s, 4H), 1.41 (t, J=7.4Hz, 3H). LRMS: calc 414.2 and found: 414.9 [M+1].

Example 105 Step 3:1-ethyl-6-fluoro-3-(2-(isoindolin-2-yl)ethyl)-1H-indol-4-ol (31-4)

To a solution of 31-3 (30 mg, 0.072 mmol) in methanol (10 mL) was added10% Pd/C (20 mg) under hydrogen atmosphere. The reaction mixture wasstirred at room temperature overnight and then filtered through a pad ofcelite. The filtrate was concentrated to give a pale yellow residue,which was purified on silica gel column chromatography eluting withdichloromethane/methanol (9:1) to give 31-4 (25 mg, 70%) as a whitesolid. ¹H-NMR (400 MHz, CDCl₃): δ (ppm) 7.29 (d, J=2.4 Hz, 2H), 7.17 (d,J=3.2 Hz, 2H), 6.76 (s, 1H), 6.50 (d, J=8.8 Hz, 1H), 6.30 (d, J=10.8 Hz,1H), 5.00-4.96 (br.s, 2H), 4.34-4.32 (br.s, 2H), 3.96 (q, 2H), 3.59-3.57(br.s, 2H), 3.32-3.30 (br.s, 2H), 1.37 (t, J=7.6 Hz, 3H). LRMS: calc324.2 and found: 325.1 [M+1].

The compounds in Table 29 were made according to processes described inScheme 31.

TABLE 29 Ex. ID Procedure Structure name number number NMR MS of scheme

N-benzyl-2- (4- (benzyloxy)- 1-ethyl-6- fluoro-1H- indol-3-yl)- N-methyl- ethanamine 107 31-6  ¹H-NMR (400 MHz, CDCl₃): δ (ppm) 7.47 (d, J= 7.2 Hz, 2H), 7.36 (t, J = 7.2 Hz, 2H), 7.31-7.26 (m, 3H), 7.25-7.22(m, 3H), 6.76 (s, 1H), 6.60 (dd, J = 9.6, 1.2 Hz, 1H), 6.34 (dd, J =11.6, 1.6 Hz, 1H), 5.11 (s, 2H), 4.00 (q, 2H), 3.42 (s, 2H), 3.08 (t, J= 7.6 Hz, 2H), 2.71 (t, J = 8.4 Hz, 2H), 2.10 (s, 3H), 1.41 (t, J = 7.2Hz, 3H). calc 416.5, found 417.0 [MH]+ 31 Step 1-2

4- (benzyloxy)- 1-ethyl-6- fluoro-3-(2- (isoindolin- 2- yl)ethyl)-1H-indole 104 31-3  ¹H-NMR (400 MHz, CDCl₃): δ (ppm) 7.46 (d, J = 7.2Hz, 2H), 7.31-7.26 (m, 4H), 7.27 (t, J = 3.6 Hz, 1H), 7.09-7.06 (m, 2H),6.93 (s, 1H), 6.65 (d, J = 7.2 Hz, 1H), 6.42 (d, J = 7.2 Hz, 1H), 5.06(s, 2H), 4.02-4.00 (m, 6H), 3.27 (s, 4H), 1.41 (t, J = 7.4 Hz, 3H). calc414.2, found 414.9 [MH]+ 31 Step 1-2

1-ethyl-6- fluoro-3-(2- (isoindolin- 2- yl)ethyl)- 1H-indol-4- ol 10531-4  ¹H-NMR (400 MHz, CDCl₃): δ (ppm) 7.29 (d, J = 2.4 Hz, 2H), 7.17(d, J = 3.2 Hz, 2H), 6.76 (s, 1H), 6.50 (d, J = 8.8 Hz, 1H), 6.30 (d, J= 10.8 Hz, 1H), 5.00-4.96 (br.s, 2H), 4.34- 4.32 (br.s, 2H), 3.96 (q,2H), 3.59-3.57 (br.s, 2H), 3.32- 3.30 (br.s, 2H), 1.37 (t, J = 7.6 Hz,3H). calc 324.2, found 325.1 [MH]+ 31

3-(2- ((1S,4S)-5- benzyl-2,5- diazabicyclo [2.2.1] heptan-2-yl)ethyl)-1- ethyl-6- fluoro-1H- indol-4-ol 108 31-7  ¹H-NMR (400 MHz,MeOD-d6): δ (ppm) 7.29- 7.21 (m, 4H), 7.16 (t, J = 7.2 Hz, 1H), 6.75 (s,1H), 6.43 (d, J = 10.0 Hz, 1H), 6.10 (dd, J = 11.6, 1.6 Hz, 1H), 3.91(q, 2H), 3.70 (d, J = 13.2 Hz, 1H), 3.60 (d, J = 12.8 Hz, 1H), 3.43 (s,1H), 3.28 (s, 1H), 3.03-2.97 (m, 2H), 2.90-2.79 (m, 4H), 2.72 (dd, J =10.8, 2.4 Hz, calc 393.4, found 394.0 [MH]+ 31 Starting from 11-3 step1-2 1H), 2.58 (dd, J = 10.4, 2.4 Hz, 1H), 1.78 (t, J = 13.2 Hz, 2H),1.26 (t, J = 7.2 Hz, 3H).

2-(4- (benzyloxy)- 1-ethyl-6- fluoro-1H- indol-3-yl)- N-(3-(tri-fluoromethyl) benzyl) ethanamine 109 31-8  ¹H-NMR (400 MHz, CDCl₃): δ(ppm) 7.45 (d, J = 7.6 Hz, 1H), 7.41-7.28 (m, 8H), 6.77 (s, 1H), 6.62(dd, J = 9.6, 1.6 Hz, 1H), 6.36 (dd, J = 11.6, 1.6 Hz, 1H), 5.05 (s,2H), 3.99-3.94 (m, 2H), 3.56 (s, 2H), 3.02 (s, 4H), 1.37 (t, J = 7.2 Hz,3H). calc 470.1, found 471.0 [MH]+ 31 Step 1-2

2-(4- (benzyloxy)- 1-ethyl-6- fluoro-1H- indol-3-yl)- N-(3-chlorobenzyl) ethanamine 110 31-9  ¹H-NMR (400 MHz, CDCl₃): δ (ppm)7.39-7.36 (m, 4H), 7.33-7.27 (m, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.10 (t,J = 7.6 Hz, 2H), 7.03 (d, J = 7.2 Hz, 1H), 6.78 (s, 1H), 6.61 (dd, J =9.6, 2.0 Hz, 1H), 6.34 (dd, J = 11.2, 1.6 Hz, 1H), 5.05 (s, 2H),3.99-3.94 (m, 2H), 3.53 (s, 2H), 3.03 (s, 4H), 1.37 (t, J = 7.2 Hz, 3H).calc 436.1, found 437.0 [MH]+ 31 Step 1-2

3-(2- (benzhydryl- amino) ethyl)-1- ethyl-6- fluoro-1H- indol-4-ol 11131-10 ¹H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.48- 7.40 (m, 10H), 6.94 (s,1H), 6.61 (dd, J = 10.0, 2.4 Hz, 1H), 6.19 (dd, J = 11.2, 1.6 Hz, 1H),5.50 (s, 1H), 4.05 (q, 2H), 3.32 (t, J = 6.8 Hz, 2H), 3.25 (t, J = 7.4Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H). calc 388.1, found 389.0 [MH]+ 31Starting from 11-3 step 1-2

3-(2-(3- chloro- benzyl- amino) ethyl)-1- ethyl-6- fluoro-1H- indol-4-ol112 31-11 ¹H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.52 (s, 1H), 7.47-7.39 (m,2H), 7.40-7.37 (m, 1H), 6.98 (s, 1H), 6.61 (dd, J = 9.6, 1.6 Hz, 1H),6.22 (dd, J = 11.2, 2.0 Hz, 1H), 4.22 (s, 2H), 4.07 (q, 2H), 3.42 (t, J= 7.4 Hz, 2H), 3.24 (t, J = 7.4 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H). calc346.1, found 346.9 [MH]+ 31 Starting from 11-3 step 1-2

1-ethyl-6- fluoro-3-(2- (3-(tri- fluoromethyl) benzylamino) ethyl)-1H-indol-4- ol 113 31-12 ¹H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.51 (s,1H), 7.45-7.42 (m, 2H), 7.37 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 6.42(dd, J = 10.0, 2.0 Hz, 1H), 6.04 (dd, J = 11.2, 1.6 Hz, 1H), 3.90 (q,2H), 3.73 (s, 2H), 2.92 (t, J = 6.4 Hz, 2H), 2.83 (t, J = 6.2 Hz, 2H),1.24 (t, J = 7.2 Hz, 3H). calc 380.4, found 381.0 [MH]+ 31

2-(4- (benzyloxy)- 1-ethyl-6- fluoro-1H- indol-3-yl)- N-(3-(tri-fluoromethyl) phenethyl) ethanamine 114 31-13 ¹H-NMR (400 MHz, MeOD-d6):δ (ppm) 7.62- 7.08 (m, 9H), 6.79 (s, 1H), 6.68 (dd, J = 9.8, 2.0 Hz,1H), 6.42 (dd, J = 11.8, 2.0 Hz, 1H), 5.12 (s, 2H), 4.00 (q, J = 7.2 Hz,2H), 2.98- 2.90 (m, 2H), 2.85-2.78 (m 2H), 2.74-2.64 (dd, J = 9.5, 5.0Hz, 4H), 1.32 (t, J = 8.5 Hz, 3H) calc 484.21, found 485.3 [MH]+ 31

Example 1152-(1-ethyl-6-fluoro-4-phenoxy-1H-indol-3-yl)-N,N-dimethylethanamine(32-2) Step 1:2-(1-ethyl-6-fluoro-4-phenoxy-1H-indol-3-yl)-N,N-dimethylethanamine(32-2)

A mixture of 1-9b (80 mg, 0.32 mmol), bromobenzene (100 mg, 0.64 mmol),K₂CO₃ (110 mg, 0.8 mmol) and CuI (152 mg, 0.8 mmol) in 10 mL of dioxanewas stirred at reflux overnight. After cooled to room temperature, thevolatiles were evaporated under vacuum and the resulting residue waspartitioned between water (10 mL) and ethyl acetate (10 mL). The organiclayer was separated and the aqueous layer was extracted with ethylacetate (3×15 mL). The organic layers were combined, washed with brine(2×30 mL), dried over MgSO₄ and evaporated. The resulting brown residuewas purified by preparative HPLC (acid condition, water/CH₃CN, 25-30%CH₃CN in 7.5 min, RT=6.5 min) to give 32-2 (3 mg, 3%) as a white solid.¹H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.34 (t, J=8.0 Hz, 2H), 7.13-7.09 (m,2H), 7.02 (d, J=8.0 Hz, 2H), 6.85 (d, J=11.2 Hz, 1H), 6.10 (d, J=11.2 Hz1H), 4.05 (q, 2H), 3.33-3.28 (m, 2H), 3.11-3.07 (m, 2H), 2.74 (s, 6H),1.33 (t, J=7.2 Hz, 3H). LRMS: calc 326.2 and found: 327.1 [M+1].

Example 1162-(4-(3-chlorobenzyloxy)-5-fluoro-1-methyl-1H-indol-3-yl)-N-methylethanamine(33-12a) Step 1: 4-(benzyloxy)-7-bromo-5-fluoro-1H-indole (17-1)

To a solution of 4-(benzyloxy)-1-bromo-2-nitrobenzene (2 g, 6.13 mmol)(prepared according patent WO2009/103710) in THF (20 mL) at −40° C. wasadded vinylmagnesium bromide (19 mL, 18.4 mmol) dropwise. Thetemperature was kept constant at 40° C. during the addition. The mixturewas stirred at this temperature for 2 h. and then saturated aqueousNH₄Cl was added to quench the reaction. The mixture was extracted withethyl acetate (3×40 mL). The combined organic layers were washed withwater (2×50 mL), dried over MgSO₄, filtered, and evaporated to afford abrown solid which was purified on silica gel column chromatographyeluting with petroleum ether/ethylacetate (5:1) to afford 17-1 (650 mg,33%) as a yellow solid. LRMS: calc 319.0 and found: 320.1 [M+1].

Step 2: 4-(benzyloxy)-7-bromo-5-fluoro-1-methyl-1H-indole (33-3)

A solution of 17-1 (9 g, 28 mmol), potassium hydroxide (2.36 g, 42 mmol)and methyl iodide (6 g, 42 mmol) in DMF (30 mL) was stirred at roomtemperature for 2 h. The mixture was poured into water (50 mL),extracted with ethyl acetate (3×50 mL). The extracts were washed withwater (3×50 mL) and brine (2×50 mL), dried over MgSO4, filtered, andevaporated to afford 33-3 (8 g, 90%) which was used directly in nextstep. LRMS: calc 333.0 and found: 334.0 [M+1].

Step 3: 2-(4-(benzyloxy)-7-bromo-5-fluoro-1-methyl-1H-indol-3-yl)aceticacid (33-4)

To the solution of 33-3 (8 g, 24 mmol) in THF (30 mL) was added oxalylchloride (15.4 g, 120 mmol) dropwised at 0° C. The mixture was stirredat room temperature overnight. The volatiles were evaporated to get ayellow residue, which was dissolved in 2,2′-oxydiethanol (50 mL). To theresulting solution were added hydrazine hydrate (6 mL) and potassiumhydroxide (6.72 g, 120 mmol). The mixture was heated at 190° C. for 2 hbefore it was cooled to room temperature. Water (100 mL) was added tothe mixture and neutralized with hydrochloric acid to pH=5, thenextracted with ethyl acetate (2×50 mL). The organic layers werecombined, washed with brine (4×50 mL), dried over MgSO₄, filtered, andconcentrated under vacuum. The resulting residue was purified on silicagel column chromatography eluting with dichloromethane/methanol (10:1)to afford 33-4 (5 g, 58%) as a yellow solid. LRMS: calc 391.0 and found:392.1 [M+1].

Step 4:2-(4-(benzyloxy)-7-bromo-5-fluoro-1-methyl-1H-indol-3-yl)-N-methylacetamide (33-5)

Following the procedure (step 1, scheme 31) used to prepare compound31-2, compound 33-4 gave compound 33-5 in 96% yield as a yellow solid.LRMS: calc 404.0 and found: 405.0 [M+1].

Step 5: 2-(5-fluoro-4-hydroxy-1-methyl-1H-indol-3-yl)-N-methylacetamide(33-6)

A mixture of 33-5 (1.4 g, 4.5 mmol), pyridine (2 mL) and Pd/C (140 mg,10%) in methanol (20 mL) was stirred at room temperature overnight underhydrogen atmosphere. The mixture was adjusted with hydrochloric acid topH=5-6. The solid was filtered off and the filtrate was concentrated.The resulting residue was partitioned between water (20 mL) andethylacetate (20 mL). The organic layer was separated, washed with brine(3×30 mL), dried over MgSO4, filtered and evaporated to obtain 33-6 (700mg, 85%) as a brown solid. LRMS: calc 236.1 and found: 237.1[M+1].

Step 6:2-(4-(3-chlorobenzyloxy)-5-fluoro-1-methyl-H-indol-3-yl)-N-methylacetamide (33-7)

A mixture of 33-6 (40 mg, 0.17 mmol), 1-(bromomethyl)-3-chlorobenzene(35 mg, 0.17 mmol) and Cesium carbonate (166 mg, 0.51 mmol) inacetonitrile (20 mL) was refluxed for 2 h. After cooled to roomtemperature, the mixture was filtered and the filtrate was evaporatedunder vacuum. The resulting residue was purified by Preparative TLC(petroleum ether/ethyl acetate=1:3) to give 33-7 (50 mg, 82%) as a whitesolid. LRMS: calc 360.1 and found: 361.1 [M+1].

Step 7:2-(4-(3-chlorobenzyloxy)-5-fluoro-1-methyl-1H-indol-3-yl)-N-methylethanamine (33-8)

A solution of 33-7 (50 mg, 0.139 mmol) in THF (10 mL) was added dropwiseinto the solution of lithium aluminum hydride (19 mg, 0.417 mmol) andAlCl₃ (41 mg, 0.381 mmol) in THF (10 mL). The mixture was stirred atroom temperature for 1 h. Na₂SO₄.10H₂O was added to quench the reaction.The solid was filtered off and washed with ethyl acetate (20 mL). Theorganic solvent was washed with brine (3×30 mL), dried over MgSO₄,filtered and evaporated. The resulting residue was purified bypreparative HPLC (acid condition, water/CH₃CN, 30-35% CH₃CN in 7.5 min,RT=6.5 min) to give 33-8 (11 mg, 23%) as a yellow solid. ¹H-NMR (400MHz, CDCl₃): δ (ppm) 8.80-8.60 (brs, 1H), 7.47 (s, 1H), 7.34 (s, 2H),7.28 (s, 1H), 7.02-6.99 (m, 1H), 6.92-6.89 (m, 2H), 5.25 (s, 2H), 3.66(s, 3H), 3.13-3.05 (m, 4H), 2.45 (s, 3H). LRMS: calc and found: 347.1[M+1].

The compounds in Table 30 were made according to processes described inScheme 33.

TABLE 30 Ex. ID Procedure Structure name number number NMR MS of scheme

2-(5-fluoro- 1-methyl-4- (quinolin-8- ylmethoxy)- 1H-indol-3- yl)-N-methyl- ethanamine 117 33-13 1H-NMR (400 MHz, MeOD-d6): δ (ppm) 8.87-8.85 (m, 1H), 8.40-8.38 (m, 1H), 7.91-7.84 (m, 2H), 7.56-7.52 (m, 2H),6.97- 6.90 (m, 3H), 5.85 (s, 2H), 3.62 (s, 3H), 2.99 (t, J = 6.8 Hz,2H), 2.82 (t, J = 7.2 Hz, 2H), 2.35 (s, 3H). calc 363.4, found 364.0[MH]+ 33

2-(5-fluoro- 1-methyl-4- (2- phenoxy- ethoxy)-1H- indol-3-yl)- N-methyl- ethanamine 118 33-14 1H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.27 (t,J = 8.0 Hz, 2H), 7.05-6.99 (m, 3H), 6.96-6.93 (m, 3H), 4.60-4.58 (m,2H), 4.32- 4.30 (m, 2H), 3.72 (s, 3H), 3.30-3.28 (m, 2H), 3.23 (t, J =5.6 Hz, 2H), 2.56 (s, 3H). calc 342.4, found 343.0 [MH]+ 33

2-(5-fluoro- 4-(4- fluorobenzyl oxy)-1- propyl-1H- indol-3-yl)- N-methyl- ethanamine 119 33-15 1H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.51-7.48 (m, 2H), 7.13-6.98 (m, 5H), 5.25 (s, 2H), 4.05 (t, J = 6.8 Hz, 2H),3.20 (t, J = 7.6, Hz, 2H), 3.08 (t, J = 6.4 Hz, 2H), 2.55 (s, 3H), 1.85-1.80 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H). calc 358.4, found 359.0 [MH]+ 33

2-(5-fluoro- 4-(4- methylbenzyl oxy)-1- propyl-1H- indol-3-yl)- N-methyl- ethanamine 120 33-16 1H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.35 (d,J = 7.6 Hz, 2H), 7.21 (d, J = 6.8 Hz, 2H), 7.10-7.00 (m, 3H), 5.22 (d, J= 3.6 Hz, 2H), 4.05 (t, J = 6.8 Hz, 2H), 3.15 (d, J = 5.6 Hz, 2H), 3.04(t, J = 6.4 Hz, 2H), 2.47 (d, J = 4.4 Hz, 3H), 2.35 (d, J = 4.4 Hz, 3H),1.84-1.81 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H). calc 354.5, found 355.0[MH]+ 33

2-(5-fluoro- l-methyl-4- (2- methylphen- ethoxy)-1H- indol-3-yl)- N-methyl- ethanamine 121 33-17 1H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.27-7.23 (m, 1H), 7.20-7.14 (m, 3H), 7.07-6.99 (m, 3H), 4.47-4.43 (m, 2H),3.73 (s, 3H), 3.17 (t, J = 7.2 Hz, 2H), 3.05 (t, J = 6.4 Hz, 2H), 2.94(t, J = 6.4 Hz, 2H), 2.57 (s, 3H), 2.35 (s, 3H). calc 340.4, found 341.1[MH]+ 33

2-(5-fluoro- 4-(4- (methyl sulfonyl) benzyloxy)- 1-propyl- 1H-indol-3-yl)-N- methyl- ethanamine 122 33-18 1H-NMR (400 MHz, MeOD-d6): δ (ppm)7.89 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.04-6.99 (m, 1H),5.30 (s, 2H), 3.97 (t, J = 6.8 Hz, 2H), 3.13 (t, J = 7.2 Hz, 2H), 3.05(t, J = 2.0 Hz, 3H), 3.02 (t, J = 7.6 Hz, 2H), 2.47 (s, 3H), 1.75-1.70(m, 2H), 0.81 (t, J = 7.2 Hz, 3H). calc 418.5, found 419.1 [MH]+ 33

2-(4-(2- chlorophen- ethoxy)-5- fluoro-1- methyl-1H- indol-3-yl)- N-methyl- ethanamine 123 33-19 1H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.45-7.40 (m, 2H), 7.29-7.27 (m, 2H), 7.06-7.01 (m, 3H), 4.49 (t, J = 6.8 Hz,2H), 3.75 (s, 3H), 3.33-3.30 (m, 2H), 3.15 (t, J = 6.4 Hz, 2H), 3.01 (t,J = 6.4 Hz, 2H), 2.62 (s, 3H). calc 360.8, found 361.1 [MH]+ 33

2-(4-(3- chloro- benzyloxy)- 5-fluoro-1- methyl-1H- indol-3-yl)- N-methyl- ethanamine 116 33-8  ¹H-NMR (400 MHz, CDCl₃): δ 8.80-8.60 (brs,1H), 7.47 (s, 1H), 7.34 (s, 2H), 7.28 (s, 1H), 7.02-6.99 (m, 1H),6.92-6.89 (m, 2H), 5.25 (s, 2H), 3.66 (s, 3H), 3.13-3.05 (m, 4H), 2.45(s, 3H). calc 346.8, found 347.1, 349.1 [MH]+ 33

2-(4-(4- chlorobenzyl oxy)-5- fluoro-1- methyl-1H- indol-3-yl)- N-methyl- ethanamine 124 33-20 ¹H-NMR (400 MHz, CDCl₃): δ (ppm) 8.78-8.90(brs, 2H), 7.35 (q, 4H), 6.98 (dd, J = 9.2, 1.2 Hz, 1H), 6.87 (dd, J =8.8, 3.2 Hz, 1H), 6.84 (s, 1H), 5.23 (s, 2H), 3.63 (s, 3H), 3.09-3.03(m, 4H), 2.41 (s, 3H). calc 346.8, found 347.1, 349.1 [MH]+ 33

2- (5-fluoro- 1-methyl-4- (3-(tri- fluoromethyl) benzyloxy)- 1H-indol-3-yl)-N- methyl- ethanamine 125 33-21 ¹H-NMR (400 MHz, CDCl₃): δ (ppm)9.10-8.90 (brs, 1H), 7.71 (s, 1H), 7.65- 7.47 (m, 3H), 7.01-6.96 (m,1H), 6.90-6.86 (m, 2H), 5.31 (s, 2H), 3.63 (s, 3H), 3.10-3.04 (m, 4H),2.39 (s, 3H). calc 380.4, found 381.1 [MH]+ 33

2-(5-fluoro- 1-methyl-4- (2- methylbenzyl oxy)-1H- indol-3-yl)- N-methyl- ethanamine 126 33-22 ¹H-NMR (400 MHz, CDCl₃): δ (ppm) 8.60-8.40(brs, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.26-7.20 (m, 3H), 7.03-6.98 (m,1H), 6.87 (dd, J = 6.0, 3.2 Hz, 1H), 6.81 (s, 1H), 5.29 (s, 2H), 3.62(s, 3H), 2.98-2.94 (m, 4H), 2.71 (s, 3H), 2.42 (s, 3H). . calc 326.4,found 327.0 [MH]+ 33

2-(4-(2- chlorobenzyl oxy)-5- fluoro-1- methyl-1H- indol-3-yl)- N-methyl- ethanamine 127 33-23 ¹H-NMR (400 MHz, CDCl₃): δ (ppm) 8.64-8.43(brs, 1H),7.57 (d, J = 3.2 Hz, 1H), 7.45 (t, J = 4.0 Hz, 1H), 7.30 (t, J= 4.0 Hz, 2H), 7.07-7.01 (m, 1H), 6.92 (dd, J = 6.0, 2.8 Hz, 2H), 5.41(s, 2H), 3.67 (s, 3H), 3.14-3.03 (m, 4H), 2.41 (s, 3H). calc 346.8,found 347.1 [MH]+ 33

2-(5-fluoro- 4-(2- fluorobenzyl oxy)-1- methyl-1H- indol-3-yl)- N-methyl- ethanamine 128 33-24 ¹H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.54-7.50 (m, 1H), 7.42-7.40 (m, 1H), 7.22-7.19 (m, 2H), 7.05-7.02 (m, 3H),5.36 (s, 2H), 3.73 (s, 3H), 3.21-3.19 (m, 2H), 3.07-3.04 (m, 2H), 2.55(s, 3H). calc 330.4, found 331.1 [MH]+ 33

2-(5-fluoro- 4-(4- methoxy- phenethoxy)- 1-methyl-1H- indol-3-yl)- N-methyl- ethanamine 129 33-25 ¹H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.22 (d,J = 8.4 Hz, 2H), 7.03-7.00 (m, 3H), 6.49 (d, J = 8.4 Hz, 2H), 4.47 (t, J= 6.6 Hz, 2H), 3.79 (s, 3H), 3.74 (s, 3H), 3.08 (t, J = 6.4 Hz, 4H),2.93 (t, J = 6.6 Hz, 2H), 2.58 (s, 3H). calc 356.4, found 357.1 [MH]+ 33

2-(5-fluoro- 1-methyl-4- phenethoxy- 1H-indol-3- yl)-N- methyl-ethanamine 130 33-26 ¹H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.34- 7.32 (m,4H), 7.28-7.24 (m, 1H), 7.05-6.99 (m, 3H), 4.52 (t, J = 6.8 Hz, 2H),3.74 (s, 3H), 3.15 (t, J = 6.8 Hz, 2H), 3.04 (t, J = 6.4 Hz, 2H), 2.89(t, J = 6.4 Hz, 2H), 2.56 (s, 3H). calc 326.4, found 327.1 [MH]+ 33

2-(5-fluoro- 1-methyl-4- (4- methyl benzyloxy)- 1H- indol-3-yl)- N-methyl- ethanamine 131 33-27 ¹H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.34 (d,J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.03 (t, J = 4.6 Hz, 3H),5.23 (s, 2H), 3.73 (s, 3H), 3.15 (t, J = 6.8 Hz, 2H), 3.02 (t, J = 6.6Hz, 2H), 2.49 (s, 3H), 2.35 (s, 3H). calc 326.4, found 327.1 [MH]+ 33

2-(5-fluoro- 4-(4- fluorophen- ethoxy)-1- methyl-1H- indol-3-yl)- N-methyl- ethanamine 132 33-28 ¹H-NMR (400 MHz, MeOD- d6): δ (ppm)7.32-7.28 (m, 2H), 7.06-6.98 (m, 5H), 4.46 (t, J = 6.6 Hz, 2H), 3.72 (s,3H), 3.14-3.09 (m, 4H), 2.97 (t, J = 6.6 Hz, 2H), 2.61 (s, 3H). calc344.4, found 345.0 [MH]+ 33

2-(4-(4- chlorophen- ethoxy)-5- fluoro-1- methyl-1H- indol-3-yl)- N-methyl- ethanamine 133 33-29 ¹H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.32-7.26 (m, 4H), 7.03-6.98 (m, 3H), 4.46 (t, J = 6.2 Hz, 2H), 3.71 (s, 3H),3.12-3.08 (m, 4H), 2.95 (t, J = 6.6 Hz, 2H), 2.60 (s, 3H). calc 360.8,found 361.1 [MH]+ 33

2-(4- (biphenyl-2- ylmethoxy)- 5-fluoro-1- methyl-1H- indol-3-yl)- N-methyl ethanamine 134 33-30 ¹H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.68-7.66 (m, 1H), 7.47-7.42 (m, 2H), 7.39-7.35 (m, 6H), 7.03-6.93 (m, 3H),5.24 (s, 2H), 3.73 (s, 3H), 3.10 (t, J = 6.8 Hz, 2H), 2.91 (t, J = 6.8Hz, 2H), 2.45 (s, 3H). calc 388.4, found 389.0 [MH]+ 33

2- (5-fluoro- 1-methyl-4- (2-(tri- fluoromethyl) benzyloxy)- 1H-indol-3- yl)-N- methyl- ethanamine 135 33-31 ¹H-NMR (400 MHz, MeOD-d6): δ(ppm) 7.83 (dd, J = 10.8, 8.0 Hz, 2H), 7.70 (t, J = 7.6 Hz, 1H), 7.57(t, J = 7.6 Hz, 1H), 7.12-7.03 (m, 3H), 5.48 (s, 2H), 3.76 (s, 3H), 3.16(t, J = 6.8 Hz, 2H), 3.01 (t, J = 6.8 Hz, 2H), 2.50 (s, 3H). calc 380.4,found 381.0 [MH]+ 33

2-(5-fluoro- l-methyl-4- (1-phenyl- ethoxy)- 1H-indol-3- yl)-N- methyl-ethanamine 136 33-32 ¹H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.42 (d, J = 6.8Hz, 2H), 7.34-7.27 (m, 2H), 7.03 (s, 1H),6.99- 6.95 (m, 2H), 5.63 (q,1H), 3.71 (s, 3H), 3.29-3.24 (m, 2H), 3.08 (t, J = 6.8 Hz, 2H), 2.60 (s,3H), 1.70 (d, J = 6.4 Hz, 3H). calc 326.4, found 327.1 [MH]+ 33

2-(5-fluoro- 4-(5-fluoro- 2-methyl- benzyloxy)- 1-methyl- 1H-indol-3-yl)-N- methyl- ethanamine 137 33-33 ¹H-NMR (400 MHz, MeOD-d6): δ (ppm)7.26- 7.19 (m, 2H), 7.08-7.00 (m, 4H), 5.25 (s, 2H), 3.74 (s, 3H), 3.17(t, J = 6.8 Hz, 2H), 3.06 (t, J = 6.8 Hz, 2H), 2.51 (s, 3H), 2.36 (s,3H). calc 344.4, found 345.1 [MH]+ 33

2-(5-fluoro- 1-methyl-4- (2-(tri- fluoro- methoxy) benzyloxy)- 1H-indol-3-yl)- N- methyl- ethanamine 138 33-34 ¹H-NMR (400 MHz, MeOD-d6):δ (ppm) 7.68 (d, J = 7.2 Hz, 1H), 7.50-7.48 (m, 1H), 7.43-7.37 (m, 2H),7.07-7.03 (m, 3H), 5.37 (s, 2H), 3.75 (s, 3H), 3.19 (t, J = 6.8 Hz, 2H),3.05 (t, J = 6.8 Hz, 2H), 2.54 (s, 3H). calc 396.4, found 397.1 [MH]+ 33

2-(5-fluoro- 4-(4- fluorobenzyl oxy)-1- methyl-1H- indol-3-yl)- N-methyl- ethanamine 139 33-35 ¹H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.48-7.44 (m, 2H), 7.11-6.99 (m, 5H), 5.22 (s, 2H), 3.70 (s, 3H), 3.20-3.16(t, J = 6.8 Hz, 2H), 3.07-3.03 (t, J = 7.0 Hz, 2H), 2.54 (s, 3H). calc330.4, found 331.1 [MH]+ 33

2-(5-fluoro- 1-methyl-4- (naphthalen- 1- ylmethoxy)- 1H-indol-3- yl)-N-methyl- ethanamine 140 33-36 ¹H-NMR (400 MHz, MeOD-d6): δ (ppm) 8.28(dd, J = 7.2, 2.0 Hz, 1H), 7.94 (t, J = 8.4 Hz, 2H), 7.60-7.53 (m, 3H),7.48 (t, J = 7.6 Hz, 1H), 7.13-7.05 (m, 2H), 6.99 (s, 1H), 5.72 (s, 2H),3.71 (s, 3H), 2.86 (t, J = 6.8 Hz, 2H), 2.77 (t, J = 6.8 Hz, 2H), 2.16(s, 3H). calc 362.4, found 363.1 [MH]+ 33

1-(2- chloro- phenyl)- 2-(5-fluoro- 1-methyl-3- (2-(methyl- amino)ethyl)-1H- indol-4- yloxy) ethano1 141 33-37 ¹H-NMR (400 MHz, MeOD-d6):δ (ppm) 7.61 (dd, J = 6.0, 1.4 Hz, 1H), 7.31-7.21 (m, 3H), 6.98 (s, 1H),6.96-6.86 (m, 2H), 5.44 (dd, J = 5.2, 2.8 Hz, 1H), 4.36-4.33 (m, 1H),4.14-4.09 (m, 1H), 3.64 (s, 3H), 3.43 (t, J = 6.0 Hz, 2H), 3.18 (t, J =6.0 Hz, 2H), 2.60 (s, 3H). calc 376.8, found 377.1, 379.1 [MH]+ 33

2- (5-fluoro- 1-methyl-4- (4-(methyl- sulfonyl) benzyloxy)- 1H-indol-3-yl)-N- methyl ethanamine 142 33-38 ¹H-NMR (400 MHz, MeOD-d6): δ (ppm)7.99 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.11-7.01 (m, 3H),5.41 (s, 2H), 3.76 (s, 3H), 3.24 (t, J = 6.8 Hz, 2H), 3.15 (s, 3H), 3.11(t, J = 6.8 Hz, 2H), 2.59 (s, 3H). calc 390.4, found 391.1 [MH]+ 33

2-(5-fluoro- 4- (naphthalen- 1- ylmethoxy)- 1-propyl-1H- indol-3-yl)- N-methyl- ethanamine 143 33-39 ¹H-NMR (400 MHz, CDCl₃): δ (ppm) 8.33 (dd,J = 7.2, 2.0 Hz, 1H), 7.99- 7.95 (m, 2H), 7.66-7.50 (m, 4H), 7.15-7.07(m, 3H), 5.78 (d, J = 1.2 Hz, 2H), 4.08 (t, J = 7.2 Hz, 2H), 2.89 (t, J= 6.8 Hz, 2H), 2.79 (t, J = 6.8 Hz, 2H), 2.16 (s, 3H), 1.84 (q, 2H),0.93 (t, J = 7.2 Hz, 3H). calc 390.4, found 391.0 [MH]+ 33

2-(4-(4- chlorobenzyl oxy)-5- fluoro-1- propyl-1H- indol-3-yl)- N-methyl- ethanamine 144 33-40 1H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.47 (d,J = 8.0 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.12-7.07 (m, 2H), 7.03-6.98(m, 1H), 5.26 (s, 2H), 4.06 (t, J = 7.0 Hz, 2H), 3.20 (t, J = 7.0 Hz,2H), 3.07 (t, J = 6.8 Hz, 2H)), 3.08 (t, J = 6.8 Hz, 2H), 2.56 (s, 3H),1.86-1.80 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H). calc 374.8, found 375.1,377.1 [MH]+ 33

2-(4-(2- chlorobenzyl oxy)-6- fluoro-1- methyl-1H- indol-3-yl)- N-methyl- ethanamine 148 33-44 ¹H-NMR(400 MHz, MeOD-d6): 6 (ppm) 7.63-7.60 (m, 1H), 7.54-7.52 (m, 1H), 7.44-7.40 (m, 2H), 6.96 (s, 1H), 6.77(dd, J = 9.6, 2.0 Hz, 1H), 6.54 (dd, J = 9.6, 2.0 Hz, 1H), 5.31 (s, 2H),3.71 (d, J = 2.0 Hz, 3H), 3.21 (t, J = 7.2 Hz, 2H), 3.11 (t, J = 6.4 Hz,2H), 2.50 (s, 3H). calc 346.8, found 347.1, 349.1 [MH]+ 33 step 4-6-7from SM 11-3

2-(4-(4- chlorobenzyl oxy)-6- fluoro-1- methyl-1H- indol-3-yl)- N-methyl- ethanamine 149 33-45 ¹H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.51 (d,J = 8.4 Hz, 2H), 7.46-7.44 (m, 2H), 6.97 (s, 1H), 6.77 (dd, J = 9.6, 2.0Hz, 1H), 6.53 (dd, J = 9.6, 2.0 Hz, 1H), 5.20 (s, 2H), 3.70 (s, 3H),3.22-3.20 (m, 2H), 3.16-3.12 (m, 2H), 2.53 (s, 3H). calc 346.8, found347.1, 349.1 [MH]+ 33 step 4-6-7 from SM 11-3

2-(4-(3- chlorobenzyl oxy)-6- fluoro-1- methyl-1H- indol-3-yl)- N-methyl- ethanamine 150 33-46 ¹H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.56 (s,1H), 7.48-7.39 (m, 3H), 6.98 (s, 1H), 6.76 (dd, J = 9.6, 2.0 Hz, 1H),6.51 (dd, J = 11.6, 1.2 Hz, 1H), 5.23 (s, 2H), 3.71 (s, 3H), 3.24 (t, J= 6.4 Hz, 2H), 3.18-3.15 (m, 2H), 2.56 (s, 3H). calc 346.8, found 347.1,349.1 [MH]+ 33 step 4-6-7 from SM 11-3

3-(2- (benzyl- amino) ethyl)-5- fluoro-1- methyl-1H- indol-4-ol 15133-47 ¹H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.46 (s, 5H), 6.99-6.93 (m,2H), 6.78 (dd, J = 8.8, 3.2 Hz, 1H), 4.23 (s, 2H), 3.72 (s, 3H), 3.43(t, J = 7.4 Hz, 2H), 3.27 (t, J = 7.4 Hz, 2H). calc 298.1, found 299.0,[MH]+ 33 step 4-6-7

2-(4-(2,4- dichloro benzyloxy)- 5-fluoro-1- methyl-1H- indol-3-yl)- N-methyl- ethanamine 152 33-48 ¹H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.60 (d,J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.39 (dd, J = 8.0 Hz, 1.6 Hz, 1H),7.10-7.01 (m, 3H), 5.37 (s, 2H), 3.75 (s, 3H), 3.23 (t, J = 6.8 Hz, 2H),3.07(t, J = 6.4 Hz, 2H), 2.58 (s, 3H). calc 380.0, found 381.0, [MH]+ 33

2-(4-(4- chloro-3- (trifluoro- methoxy) benzyloxy)- 5-fluoro-1-methyl-1H- indol-3-yl)- N-methyl- ethanamine 153 33-49 ¹H-NMR (400MHz, MeOD-d6): δ (ppm) 7.60 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.48 (dd,J = 8.0 Hz, 1.6 Hz, 1H), 7.11-7.01 (m, 3H), 5.32 (s, 2H), 3.76 (s, 3H),3.24 (t, J = 6.8 Hz, 2H), 3.10 (t, J = 6.8 Hz, 2H), 2.01 (s, 3H). calc430.1, found 431.0, [MH]+ 33

Example 1552-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)-N-(thiophen-2-ylmethyl)ethanamine(34-6) Step 1: 2-(4-(benzyloxy)-7-bromo-5-fluoro-H-indol-3-yl)aceticacid (34-2)

Following the procedure (step 3, scheme 33) used to prepare compound33-4, compound 17-1 gave compound 34-2 in 58% yield as a yellow solidafter column chromatography on silica gel eluting withdichloromethane/methanol (5:1). LRMS: calc 377.0 and found: 378.0 [M+1].

Step 2: 2-(5-fluoro-4-hydroxy-1H-indol-3-yl)acetic acid (34-3)

Following the procedure (step 9, scheme 13) used to prepare compound33-10, compound 34-2 gave compound 34-3 in 90% yield as a yellow solid.The crude product was used in the next step without purification. LRMS:calc 209.2 and found: 210.1 [M+1].

Step 3: 2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)acetic acid (34-4)

A mixture of compound 34-3 (1 g, 4.78 mmol), KOH (1 g, 19.14 mmol), MeI(2.7 g, 19.14 mmol) in DMF (20 mL) was stirred at room temperature for 2h. Water (50 mL) and ethyl acetate (50 mL) were added to the mixture.The organic layer was separated and the aqueous layer was extracted withethyl acetate (3×30 mL). The organic layers were combined, dried overMgSO₄, filtered, and evaporated to afford crude product (600 mg). Tothis crude product was added methanol (10 mL) and NaOH aq. (2 N, 8 mL)and then the reaction mixture was stirred and refluxed for 1 h. Themixture was allowed to cool to room temperature and neutralized withhydrochloric acid to pH=7 before it was extracted with ethyl acetate(2×30 mL). The organic layers were combined, dried over MgSO₄, filtered,and concentrated under reduce pressure to afford 34-4 (250 mg, 85%) asyellow oil. LRMS: calc 237.2 and found: 238.1 [M+1].

Step 4:N2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)-N-(thiophen-2-ylmethyl)acetamide(34-5)

Following the procedure (step 4, scheme 33) used to prepare compound33-5, compound 34-4 gave compound 34-5 in 82% yield as yellow solid.LRMS: calc 332.1 and found: 333.0 [M+1].

Step 5:2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)-N-(thiophen-2-ylmethyl)ethanamine(34-6)

Following the procedure (step 7, scheme 33) used to prepare compound33-8, compound 34-5 gave compound 34-6. ¹H-NMR (400 MHz, MeOD-d6): δ(ppm) 7.57 (d, J=4.8 Hz, 1H), 7.30 (d, J=3.6 Hz, 1H), 7.13-7.09 (m, 2H),7.05-6.97 (m, 2H), 4.48 (s, 2H), 4.01 (d, J=2.4 Hz, 3H), 3.75 (s, 3H),3.38-3.33 (m, 2H), 3.21 (t, J=7.4 Hz, 2H). LCMS calc 318.1. found 319.0[MH]+.

The compounds in Table 31 were made according to processes described inScheme 34.

TABLE 31 Ex. ID Procedure Structure name number number NMR MS of scheme

2-(5-fluoro- 4-methoxy- 1-melhyl- 1H-indol-3- yl)-N- (thiophen-2-ylmethyl) ethanamine 154 34-6  ¹H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.57(d, J = 4.8 Hz, 1H), 7.30 (d, J = 3.6 Hz, 1H), 7.13-7.09 (m, 2H),7.05-6.97 (m, 2H), 4.48 (s, 2H), 4.01 (d, J = 2.4 Hz, 3H), 3.75 (s, 3H),3.38- 3.33 (m, 2H), 3.21 (t, J = 7.4 Hz, 2H). calc 318.1, found 319.0[MH]+ 34

N-(3,4- dimethoxy- benzyl)-2- (5-fluoro-4- methoxy-1- methyl-1H-indol-3- yl) ethanamine 156 34-8  ¹H-NMR (400 MHz, MeOD-d6): δ (ppm)7.07- 7.00 (m, 6H), 4.17 (s, 2H), 4.00 (d, J = 2.0 Hz, 3H), 3.86 (d, J =5.2 Hz, 6H), 3.75 (s, 3H), 3.34-3.32 (m, 2H), 3.20 (t, J = 7.6 Hz, 2H).calc 372.1, found 373.0 [MH]+ 34

2-(2-(5- fluoro-4- methoxy-1- methyl-1H- indol-3- yl)ethyl- amino)-2-phenyl- ethanol 157 34-9  ¹H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.40- 7.30(m, 5H), 6.99-6.94 (m, 1H), 6.88-6.84 (m, 2H), 5.38-5.30 (br.s, 1H),5.33- 5.30 (m, 1H), 4.16-4.08 (m, 2H), 3.91 (d, J = 2.8 Hz, 4H), 3.68(s, 3H), 3.16 (s, 4H). calc 342.1, found 343.0 [MH]+ 34

2-(5-fluoro- 4-methoxy- 1-methyl- 1H-indol-3- yl)-N-(1- phenylethyl)ethanamine 158 34-10 ¹H-NMR (400 MHz, MeOD-d6): δ (ppm) 7.50- 7.44 (m,5H), 7.02-6.94 (m, 3H), 4.42 (q, 1H), 3.89 (d, J = 2.8 Hz, 3H), 3.72 (s,3H), 3.24-3.10 (m, 4H), 1.70 (d, J = 6.4 Hz, 3H). calc 326.1, found327.0 [MH]+ 34

Example 1602-((3-(2-((2-cyanobenzyl)(methyl)amino)ethyl)-5-fluoro-1-methyl-1H-indol-4-yloxy)methyl)benzonitrile(35-2) Step 1-2:2-((3-(2-((2-cyanobenzyl)(methyl)amino)ethyl)-5-fluoro-1-methyl-1H-indol-4-yloxy)methyl)benzonitrile(35-2)

Following the procedure (step 7, scheme 33) used to prepare compound33-8, compound 33-6 gave 85% yield of a amine, which used in the nextstep without further purification.

Following the procedure (step 6, scheme 33) used to prepare compound33-7, the crude amine gave compound 35-2 in 60% yield as a white solidafter purification by preparative HPLC. ¹H-NMR (400 MHz, MeOD-d6): δ(ppm) 7.85-7.82 (m, 2H), 7.71-7.64 (m, 4H), 7.56-7.51 (m, 2H), 7.18 (s,1H), 7.13-7.03 (m, 2H), 5.42 (s, 2H), 4.48-4.37 (m, 2H), 3.77 (s, 3H),3.59-3.50 (m, 2H), 3.26 (t, J=7.4 Hz, 2H), 2.84 (s, 3H). LRMS: calc452.2. found 453.0 [MH]+.

Example 1612-(1-ethyl-4-methoxy-6-phenyl-1H-indol-3-yl)-N,N-dimethylethanamine(36-6) Step 1: 6-bromo-1-ethyl-4-methoxy-1H-indole (36-2)

NaH (96 mg, 4 mmol) was suspended in 7 mL DMF in a round bottom flaskand cooled to 0° C. 6-bromo-4-methoxy-1H-indole (0.75 g, 3.3 mmol) wasadded dropwise as a solution in DMF (1 mL). Ethyl iodide (0.28 mL, 3.5mmol) was added dropwise and the reaction mixture was stirred for 10min. Volatiles were removed under reduced pressure and the residuepartitioned between DCM and water. The aqueous layer was extracted withDCM and the combined organics layers were dried over MgSO₄, filtered,and evaporated to give a red oil. The resulting residue was purified onsilica gel column chromatography eluting with hexanes/ethyl acetate(0-10%) to afford pure 36-2 (584 mg, 70%) as a white solid.

Step 2:2-(6-bromo-1-ethyl-4-methoxy-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide(36-3)

Following the procedure (step 5, scheme 1) used to prepare compound1-6a, compound 36-2 gave compound 36-3 (669 mg, 88%) as a pale pinksolid. LCMS: calc 352.0 and found: 353.0 [MH]⁺.

Step 3:2-(1-ethyl-4-methoxy-6-phenyl-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide(36-4)

To a sealable vessel was added 36-3 (100 mg, 0.28 mmol), phenylboronicacid (1042 mg, 0.86 mmol), Pd(PPh₃)₄ (66 mg, 10 mol %), and potassiumcarbonate (117 mg, 0.85 mmol). Dioxane (1.5 mL) was added and thereaction heated at 100° C. two days. The reaction mixture was dilutedwith ethyl acetate, filtered through celite and concentrated. Theresulting residue was purified on silica gel column chromatographyeluting with hexanes/ethylacetate (50-100%) to afford 79 mg of 36-4.LCMS: calc 350.2 and found: 351.1 [MH]⁺.

Step 4:2-(dimethylamino)-1-(1-ethyl-4-methoxy-6-phenyl-1H-indol-3-yl)ethanol(36-5)

Following the procedure (step 6, scheme 1) used to prepare compound1-7a, compound 36-4 gave compound 36-5 (68%), which was taken on to thefinal step without further purification. LCMS: calc 338.2 and found:313.1 [MH−water]⁺.

Step 5:2-(1-ethyl-4-methoxy-6-phenyl-1H-indol-3-yl)-N,N-dimethylethanamine(36-6)

36-5 (68 mg, 0.2 mmol) was dissolved in DCM (2 mL) and triethylsilane(0.32 mL, 2.0 mmol) was added at 0° C. Trifluoroacetic acid (126 uL, 1.6mmol) was added dropwise. After 20 minutes, the reaction mixture wasquenched with saturated aqueous sodium bicarbonate and then diluted withDCM. The organic layer was dried over MgSO₄, filtered, and evaporated.The resulting residue was purified on silica gel column chromatographyeluting with DCM/methanol (0-10%) containing 0.1% NH₄OH to give thedesired product. The product was acidified with HCl to afford 36-6 (19.6mg, 27%) as an off-white solid. ¹H NMR (300 MHz, D₂O): δ (ppm) 7.62 (m,2H), 7.42-7.24 (m, 4H), 7.06 (s, 1H), 6.78 (s, 1H), 4.04 (q, J=7.5 Hz,2H), 3.88 (s, 3H), 3.31 (t, J=8.4 Hz, 2H), 3.12 (t, J=7.5 Hz, 2H), 2.76(s, 6H), 1.24 (s, 7.5 Hz, 3H). LCMS: calc 322.4 and found: 323.1 [MH]⁺.

Example 1624-(benzyloxy)-1-ethyl-6-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole(37-3) Step 1:4-(benzyloxy)-1-ethyl-6-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole(37-3)

In pressure vessel, tert-butyl 4-oxopiperidine-1-carboxylate (370 mg,1.86 mmol) was dissolved in acetic acid (3 mL) and then4-(benzyloxy)-1-ethyl-6-fluoro-1H-indole (200 mg, 0.74 mmol) was added,followed by trifluoroacetic acid (1 mL). The reaction mixture was heatedto 80° C. for 1 hour. Volatils were evaporated and then water was added.The pH was adjusted to ˜12 with 15% aqueous NaOH and partitioned betweenEtOAc-water. The organic layer was washed with brine, dried over MgSO₄,filtered and concentrated to give a crude product. The resulting residuewas purified on alumina column chromatography eluting with DCM/methanol(0-6%) to afford 37-3 (84 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ (ppm)8.78 (br. s, 2H), 7.51-7.41 (m, 5H), 7.27 (s, 1H), 6.99 (dd, J=9.9 Hzand 2.1 Hz, 1H), 6.63 (dd, J=11.8 Hz and 2.1 Hz, 1H), 5.84, (br. s, 1H),5.16 (s, 2H), 4.11 (q, J=7.2 Hz, 2H), 3.46 (br. s, 2H), 2.93 (br.s, 2H),2.61 (br. s, 2H), 1.31 (t, J=7.2 Hz, 3H). LCMS: calc 350.4 and found:351.1 [MH]⁺.

Example 163 1-ethyl-6-fluoro-3-(piperidin-3-yl)-1H-indol-4-ol (38-4)Step 1:3-(1-benzyl-1,4,5,6-tetrahydropyridin-3-yl)-4-(benzyloxy)-1-ethyl-6-fluoro-1H-indole(38-3)

Following the procedure (step 1, scheme 37) used to prepare compound37-3, compound 37-1 gave compound 38-3 (98%) as a brown oil that wastaken on to the next step without purification. LCMS: calc 440.2 andfound: 439.3 [MH]⁻.

Example 163 Step 2: 1-ethyl-6-fluoro-3-(piperidin-3-yl)-1H-indol-4-ol(38-4)

Following the procedure (step 3 scheme 31 used to prepare compound 31-4compound 38-3 gave compound 38-4 (113 mg, 59%) as a light tan-coloredsolid. ¹H NMR (300 MHz, MeOD-d6): δ (ppm) 6.80 (s, 1H), 6.49 (dd,J=10.0, 2.1 Hz, 1H), 6.13 (dd, J=11.4, 2.1 Hz, 1H), 4.01 (q, J=7.2 Hz,2H), 3.53-3.40 (m, 2H), 3.05 (d, J=11.4 Hz, 1H), 2.55 (dt, J=23.0, 11.7Hz, 2H), 2.14 (dd, J=8.8, 6.1 Hz, 1H), 1.85-1.56 (m, 3H), 1.34 (t, J=7.2Hz, 3H). LCMS: calc 262.1 and found: 263.1 [MH]⁺.

Example 164 1-ethyl-6-fluoro-3-(1-methylpiperidin-3-yl)-1H-indol-4-ol(38-6) Step 3: tert-butyl3-(1-ethyl-6-fluoro-4-hydroxy-1H-indol-3-yl)piperidine-1-carboxylate(38-5)

38-4 (350 mg, 1.1 mmol) was dissolved in DCM (6 mL) anddi-tert-butyl-dicarbonate (284 mg, 1.3 mmol) was added. The reactionmixture was stirred at room temperature for 30 minutes and then dilutedwith DCM, washed with aqueous sodium bicarbonate, dried over MgSO₄,filtered and concentrated to give the crude product. The resultingresidue was purified on silica gel column chromatography eluting withhexanes/ethylacetate (5-30%) to afford 224 mg (57%) of 38-5 as a whitecrystalline solid. LCMS: calc 362.2 and found: 363.2 [MH]⁺.

Step 3: 1-ethyl-6-fluoro-3-(1-methylpiperidin-3-yl)-1H-indol-4-ol (38-6)

Following the procedure (step 6, scheme 1) used to prepare compound1-7a, compound 38-5 gave compound 38-6 (20 mg, 22%) as a white solid. 1HNMR (300 MHz, DMSO-d6) δ (ppm) 9.91 (s, 1H), 6.92 (s, 1H), 6.63 (dd,J=10.2, 2.1 Hz, 1H), 6.14 (dd, J=11.5, 2.1 Hz, 1H), 3.98 (q, J=7.1 Hz,2H), 3.31 (m, 1H), 3.02 (d, J=10.1 Hz, 1H), 2.71 (s, 1H), 2.14 (s, 3H),2.01-1.42 (m, 5H), 1.25 (m, J=7.2 Hz, 4H). LCMS: calc 276.2 and found:277.1 [MH]⁺.

Example 165N-benzyl-2-(1-ethyl-6-fluoro-4-methoxy-1H-indol-3-yl)ethanamine (39-4)Step 1: 1-ethyl-6-fluoro-3-(2-hydroxyethyl)-1H-indol-4-ol (39-2)

Following the procedure (step 3 scheme 31 used to prepare compound 31-4compound 26-5 gave compound 39-2 (318 mg, 99%) as a light purple solid.

Step 2: 2-(1-ethyl-6-fluoro-4-methoxy-1H-indol-3-yl)ethanol (39-3)

39-2 (318 mg, 1.43 mmol) was dissolved in DMF (5 mL) and then potassiumcarbonate (236 mg, 1.71 mmol) and methyl iodide (98 uL, 1.56 mmol) wereadded. The reaction mixture was stirred at room temperature overnight,concentrated under vacuum and then water added. A solid was filtered toafford 39-3 (313 mg, 90%) as a light purple solid. LCMS: calc 326.2.found 327.1 [MH]⁺.

Step 3-4:N-benzyl-2-(1-ethyl-6-fluoro-4-methoxy-1H-indol-3-yl)ethanamine (39-4)

Following the procedure used to prepare compound 23-4a (scheme 23, step3-4), compound 39-4 was prepared from 39-3. Compound 39-4 was obtainedas yellow oil (26 mg, 40%). ¹H NMR (300 MHz, DMSO-d6) δ (ppm) 7.31-7.15(m, 5H), 6.95 (s, 1H), 6.82 (dd, J=10.1, 2.0 Hz, 1H), 6.34 (dd, J=12.1,2.0 Hz, 1H), 4.01 (t, J=7.2 Hz, 2H), 3.77 (s, 3H), 3.70 (s, 2H), 2.86(t, J=6.6 Hz, 2H), 2.71 (t, J=7.4 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H). LCMS:calc 326.18. found 327.1 [MH]+.

The compounds in Table 33 were made according to processes described inScheme 39.

TABLE 33 Ex. ID Procedure Structure name number number NMR MS of scheme

2-(1-ethyl-6- fluoro-4- methoxy-1H- indol-3-yl)- N-(2-(1- ethyl-6-fluoro-4- methoxy-1H- indol-3- yl)ethyl)-N- methyl- ethanamine 166 39-5¹H NMR (300 MHz, MeOD-d6): δ (ppm) 6.86 (s, 2H), 6.66 (dd, J = 9.8, 2.0Hz, 2H), 6.31 (dd, J = 11.9, 2.0 Hz, 2H), 4.10- 3.97 (m, 4H), 3.81 (s,6H), 3.03 (dd, J = 10.2, 6.1 Hz, 4H), 2.79 (dd, J = 10.2, 5.9 Hz, 4H),2.48 (s, 3H), 1.35 (s, 6H) calc 469.25, found 470.2 [MH]+ 39 Startingmaterial 0.5 eq MeNH2

1-ethyl-6- fluoro-3-(2- (2- phenylpropyl amino) ethyl)-1H- indol-4-ol166b 39-6 ¹H NMR (300 MHz, MeOD-d6): δ (ppm) 7.24- 7.01 (m, 5H), 6.64(s, 1H), 6.48 (dd, J = 10.0, 2.1 Hz, 1H), 6.14 (dd, J = 11.5, 2.1 Hz,1H), 3.94 (q, J = 7.2 Hz, 2H), 3.05-2.68 (m, 7H), 1.29 (t, J = 7.2 Hz,3H), 1.20 (d, J = 6.9 Hz, 3H). calc 340.2, found 341.2 [MH]+

Example 1672-(7-propyl-3,7-dihydro-2H-[1,4]dioxino[2,3-e]indol-9-yl)ethanamine(40-7) Step 1: 6-bromo-3,7-dihydro-2H-[1,4]dioxino[2,3-e]indole (40-2)

Following the procedure (step 1, scheme 33) used to prepare compound17-1, compound 40-1 gave compound 40-2 in 35% yield as a yellow solid.LCMS: calc 253.0. found 254.8 [MH]+.

Step 2: 6-bromo-7-propyl-3,7-dihydro-2H-[1,4]dioxino[2,3-e]indole (40-3)

Following the procedure (step 2, scheme 33) used to prepare compound33-3, compound 40-2 gave compound 40-3 in 90% yield as a yellow solid.LCMS: calc 295.0. found 296.0 [MH]+.

Step 3:2-(6-bromo-7-propyl-3,7-dihydro-2H-[1,4]dioxino[2,3-e]indol-9-yl)aceticacid (40-4)

Following the procedure (step 3, scheme 333) used to prepare compound33-4, compound 40-3 gave compound 40-4 in 74% yield as a yellow solid.LCMS: calc 353.0. found 353.9 [MH]+.

Step 4: 2-(7-propyl-3,7-dihydro-2H-[1,4]dioxino[2,3-e]indol-9-yl)aceticacid (40-5)

A mixture of 40-4 (0.16 g, 0.45 mmol), NaOAc (0.9 g, 0.74 mmol) and 10%Pd/C (0.2 g) in ethyl acetate (20 mL) was stirred under H₂ at roomtemperature for 12 h. The solid was filtered off and the filtrate wasconcentrated to obtain the desired product 40-5 (0.12 g, 97%) as ayellow solid, which was used in the next step without furtherpurification. LCMS: calc 275.0. found 276.0 [MH]⁺.

Step 5:2-(7-propyl-3,7-dihydro-2H-[1,4]dioxino[2,3-e]indol-9-yl)acetamide(40-6)

Following the procedure (step 1, scheme 31) used to prepare compound31-2, compound 40-5 gave compound 40-6 in 100% yield as yellow oil.LCMS: calc 274.1. found 275.0 [MH]⁺.

Step 6:2-(7-propyl-3,7-dihydro-2H-[1,4]dioxino[2,3-e]indol-9-yl)ethanamine(40-7)

Following the procedure (step 6, scheme 1) used to prepare compound1-7a, compound 40-6 gave compound 40-7 (5 mg, 9%) as yellow oil. ¹H NMR(300 MHz, MeOD-d6): δ (ppm) 6.87 (s, 1H), 6.73 (d, J=8.8 Hz, 1H), 6.61(d, J=8.8 Hz, 1H), 4.26-4.24 (m, 2H), 4.16-1.15 (m, 2H), 3.91 (t, J=7.2Hz, 2H), 3.13 (t, J=7.2 Hz, 2H), 3.02 (t, J=7.2 Hz, 2H), 1.71 (q, J=7.2Hz, 2H), 0.80 (t, J=7.2 Hz, 3H). LCMS: calc 260.2. found 261.1 [MH]⁺.

Example 41 LCMS Methods

Standard conditions for Analytical LCMS conditions are as follows:Standard Conditions Column type: Waters Symmetry C18 100×4.6 mm IC, 3.5μmRun time: 10.00 minute runQC Conditions Column type: Waters symmetry C18 50×4.6 mm ID, 3.5 μmRun time: 5.00 minute run

NH₄OAc (AA) Standard Conditions: NH₄OAc (AA) QC conditions: Solvent A:Solvent A: 10 mM NH₄OAc 10 mM NH₄OAc 98% water 99% water 2% Isopropylalcohol 1% MeCN Solvent B: Solvent B: 10 mM NH₄OAc 10 mM NH₄OAc 25%Methanol 5% water 75% MeCN 95% MeCN

HCOOH (FA) Standard and OC Conditions: Solvent C: 0.1% HCOOH

99% water

1% MeCN Solvent D: 0.1% HCOOH

5% water

95% MeCN Standard Gradient (Ammonium Acetate and Formic AcidConditions):

Time Solvent Solvent Flow rate [min] A % B % [ml/min] 0.00 95.0 5.0 1.07.50 0.0 100.0 1.0 8.00 0.0 100.0 1.0 9.75 0.0 100.0 1.0 9.80 95.0 5.01.0 10.00 95.0 5.0 1.0

QC Gradient (Ammonium Acetate and Formic Acid Conditions):

Time Solvent Solvent Flow rate [min] A % B % [ml/min] 0.00 95.0 5.0 1.03.50 0.0 100.0 1.0 4.90 0.0 100.0 1.0 5.0 95.0 5.0 1.0System: Agilent 1200 HPLC/MSD, DAD Wavelength Range (nm) detector; A6110Quadrupole MS, electrospray ion source (ESI).

1.QA Project LCMS/HPLC Base Methods

Column XBridge C18 4.6 × 150 mm, 3.5 μm Solvent A Water (10 mM NH₄HCO3)Solvent B MeCN Col Temp 40 degrees centigrade Split ratio ELSD:MS 10:1DAD Wavelength Range (nm) 210 to 350 Mass range 100 to 1000

Gradient

Time (min) Solvent A % Solvent B % Flow rate (mL/min) 0.0 80.0 20.0 1.21.5 80.0 20.0 1.2 8.0 20.0 80.0 1.2 8.1 5.0 95.0 1.2 16.0 5.0 95.0 1.2

2 QA Project LCMS/HPLC Acid Method

Column Agilent Eclipse XDB-C18 (4.6 × 150 mm, 5 μm) Solvent A Water(0.01% TFA) Solvent B MeCN(0.01% TFA) Col Temp 35 degrees centigradeSplit ratio ELSD:MS 10:1 DAD Wavelength Range (nm) 210 to 350 mass range100 to 1000 amu

Gradient

Time (min) Solvent A % Solvent B % Flow rate (mL/min) 0.0 80.0 20.0 1.21.5 80.0 20.0 1.2 8.0 20.0 80.0 1.2 8.1 5.0 95.0 1.2 16.0 5.0 95.0 1.2

Example 42 Preparative HPLC Methods

Instrument Glison 281(PHG005) Column Waters Sunfire Prep C18 OBD, 30 *100 mm, 5 um Wavalength(nm) 214/254 Flow Rate(ml/min) 30.00 Method Acidcondition Basic condition Mobile Phase A: Water(0.05% TFA), : Water(0.1%NH3H2O); B: ACN B: ACN(0.1% NH3H2O) Gradient % B in 7.5 min, stop at % Bin 7.5 min, stop at 12 min 12 min

Example 43 Aequorin Assays Dose Response Testing Protocol:

For Aequorin technology Aequorin human serotonin 5-HT2A, 5-HT2C(e) and5-HT2C(ne) cells grown 18 hours prior to the test in media withoutantibiotics are detached by gentle flushing with PBS-EDTA (5 mM EDTA),recovered by centrifugation and resuspended in “assay buffer”(DMEM/HAM's F12 with HEPES+0.1% BSA protease free). Cells are incubatedat room temperature for at least 4 h with Coelenterazine h (MolecularProbes). Dose response curves with the reference compounds are performedbefore testing the compounds. 5-HT2A reference agonist and antagonistare -methyl-5-HT and ketanserin, respectively. 5-HT2C(e) and 5-HT2C(ne)reference agonists are -methyl-5-HT and 5-HT, respectively. 5-HT2C(e)and 5-HT2C(ne) reference antagonist is RS102221. For agonist testing, 50μl of cell suspension will be injected on 50 μl of test compound orreference agonist plated in a 96-well plate. The resulting emission oflight will be recorded using the Hamamatsu Functional Drug ScreeningSystem 6000 (FDSS 6000). Following an incubation of 15 min after thefirst injection, 100 μl of the reference agonist at a concentrationcorresponding to its EC80 will be injected on the 100 μl of the mixtureof cell suspension and test compound, for antagonist testing. Theresulting emission of light will be recorded using FDSS6000. Tostandardize the emission of recorded light (determination of the “100%signal”) across plates and across different experiments, some of thewells will contain 100 μM digitonin or a saturating concentration of ATP(20 μM). Plates will also contain the reference agonist at aconcentration equivalent to the EC80 obtained during the testvalidation. Agonist activity of test compound will be expressed as apercentage of the activity of the reference agonist at its EC100concentration. Antagonist activity of test compound will be expressed asa percentage of the inhibition of reference agonist activity at its EC80concentration.

Example 44 cAMP Assays Dose Response Testing Protocol:

Recombinant 5-HT6 cells grown to mid-log phase in culture media withoutantibiotics are detached with PBS-EDTA, centrifuged and resuspended inassay buffer (KRH, 1 mM IBMX) at a concentration of 2.1×105 cells/ml.The test is performed in 96 well plates. For agonist testing, 12 μl ofcells (2,500 cells/well) are mixed with 12 μl of test compound atincreasing concentrations. For antagonist testing, 12 μl of cells (2,500cells/well) are mixed with 6 μl of the test compound at increasingconcentrations. After incubation for 10 min at room temperature, 6 μl ofthe reference agonist are added at a final agonist concentrationcorresponding to the historical EC80. The plates are then incubated for30 min at room temperature. After addition of the lysis buffer, cAMPconcentrations are estimated, according to the manufacturerspecification, with the HTRF kit from Cis-Bio International (catn^(o)62AM2PEB). 5-HT6 reference agonist and antagonist are 5-HT andmianserin, respectively.

Quality Control for Compound Testing:

On each day of experimentation and prior to the testing of compounds,reference compounds were tested at several concentrations in duplicate(n=2) to obtain a dose-response curve and an estimated EC50 and/or IC50values. Reference values thus obtained for the test will be compared tohistorical values obtained from the same receptor and used to validatethe experimental session. A session was considered as valid only if thereference value was found to be within a 0.5 logs interval from thehistorical value. For replicate determinations, the maximum variabilitytolerated in the test will be of +/−20% around the average of thereplicates.

The disclosures of each and every patent, patent application andpublication cited herein are hereby incorporated herein by reference intheir entirety.

Although the invention has been disclosed with reference to specificembodiments, it is apparent that other embodiments and variations of theinvention may be devised by others skilled in the art without departingfrom the true spirit and scope of the invention. The claims are intendedto be construed to include all such embodiments and equivalentvariations.

Example 45 cAMP Agonist and Antagonist Mode at 5-HT6

For assessment of 5-HT6 activity, 1321N1 cells stably expressing human5-HT6 were grown to −90% confluence in a humidified atmosphere at 37° C.with 5% CO₂ in F12 nutrient mixture (Ham) containing 10% dialyzed FBS,400 g/ml G418, 100 U/ml penicillin, and 100 g/ml streptomycin. Mediumwas removed by aspiration, cells were washed 1× with PBS, anddissociated using PBS-EDTA for 5 min at room temperature. Cells werethen diluted with PBS and pelleted by centrifugation for 5 min at 1000rpm. Cells were suspended in assay buffer containing 300 M Ro-20-1724(Sigma, St. Louis, Mo.), a phosphodiesterase inhibitor. Cells wereseeded using a microplate dispenser at a density of 3,750 cells/well ina volume of 5 μl onto 384 well white wall/opaque bottom, small volumeplates (Greiner Bio One, Monroe, N.C.).

Compound plates for cAMP assays were prepared at 8 mM in 100% DMSO anddiluted in assay buffer to the appropriate test concentrations. Thefinal in-well concentration of DMSO was 0.5%. Compounds were tested induplicate wells using a range of twelve concentrations.

Test compounds were transferred to assay plates using an automatedliquid handling workstation (Janus; PerkinElmer, Waltham, Mass.). Afterthe addition of test compounds, plates were incubated for 15 min in ahumidified atmosphere at 37° C. with 5% CO₂. After that, either assaybuffer (for agonist mode) or the EC₈₀ (15 nM in assay buffer) of 5-HT(for antagonist mode) was added, and the plates incubated for anadditional 30 min in a humidified atmosphere at 37° C. with 5% CO₂.

Homogeneous time-resolved fluorescence (HTRF) (cAMP dynamic 2 kit;Cisbio, Bedford, Mass.) was used to measure the formation of3′,5′-cyclic adenosine monophosphate (cAMP) per the manufacturer'sinstructions. HTRF signal was measured at 620 and 665 nm using anEnVision Multilabel Plate Reader (PerkinElmer). Compounds were firsttested in agonist mode, with E_(max) defined as percent activationrelative to the EC₁₀₀ (10 M) of 5-HT. Only compounds lacking significant(i.e. <25%) activity in agonist mode were tested in antagonist mode.Maximum inhibition (I_(max)) in antagonist mode was defined as percentinhibition relative to 10 M of a 5-HT6 antagonist reference compound (SB258585; Tocris, Ellisville, Mo.). Minimum inhibition in antagonist modewas defined by the EC₈₀ (15 nM) of 5-HT.

Example 46 Binding Assay 5-HT2A, 5-HT2B, 5-HT2C(VSV) and 5-HT6 (Agonistand Antagonist Ligand)

All radioligand binding assays were performed at Euroscreen SA(Gosselies, Belgium). Membrane extracts were prepared at Euroscreen fromChinese Hamster Ovary (CHOK1) cells stably expressing human 5-HT2A,5-HT2B, 5-HT2C(VSV), or 5-HT6 using standard methods. Compounds weresolubilized in 100% DMSO at a concentration of 10 mM (master solution).Serial dilutions were made from master solutions in 100% DMSO to obtainintermediate concentrations 200-fold higher than the finalconcentrations to be tested. Each sample was then diluted 100-fold inthe appropriate assay buffer (see below) and dispensed onto the testplate. Compounds were tested in duplicate wells in 8 point dose-responsecurves at the following concentrations: 0.00001, 0.0001, 0.001, 0.01,0.1, 1, 10, and 100 M. The competitive displacement of radioligand wasused to measure the IC₅₀ of test compound. IC₅₀s were converted toabsolute inhibition constants (Kis) using the Cheng-Prusoff equation.

Human 5-HT2A radioligand binding assays were performed by the successiveaddition of 1) 50 μl of either test compound or reference ligand (5-HT)at increasing concentrations, 2) 25 μl of either diluted agonist([¹²⁵I]DOI; Perkin Elmer ET62690) or antagonist ([3H]ketanserin; PerkinElmer NET-791) radioligand, and 3) 25 μl membrane extracts (5 g/well)into the wells of a 96 well plate (Master Block; Greiner Bio One). Allnecessary dilutions were made in assay buffer (50 mM Tris, 5 mM CaCl2,0.1% ascorbic acid, pH 7.4). The final concentrations of [¹²⁵I]DOI and[3H]ketanserin were 0.4 and 1 nM, respectively. Plates were incubatedfor 60 min at 25° C. in a water bath, and then filtered over GF/Bfilters (Perkin Elmer) presoaked for 2 hr at room temperature in 0.5%polyethyleneimine (PEI) with a Filtermate Harvester (PerkinElmer).Filters were washed 3× with 0.5 ml of ice-cold wash buffer (50 mM Tris).50 μl of Microscint 20 (Packard Instrument, Meriden, Conn.) was thenadded, the plates were incubated for 15 min at room temperature on anorbital shaker, and counted using either a TopCount™ or MicroBeta™(PerkinElmer) for 1 min/well.

Human 5-HT2B radioligand binding assays were performed by the successiveaddition of 1) 50 μl of either test compound or reference ligand (5-HTand methysergide) at increasing concentrations, 2) 25 μl of eitherdiluted agonist ([¹²⁵I]DOI) or antagonist ([H]mesulergine; AmershamTRK845) radioligand, and 3) 25 μl membrane extracts (7 g/well) into thewells of a 96 well plate. All necessary dilutions were made in assaybuffer (50 mM Tris, 4 mM CaCl2, 0.1% ascorbic acid, pH 7.4). The finalconcentrations of [¹²⁵I]DOI and [3H]mesulergine were 0.2 and 1 nM,respectively. Plates were incubated for 30 min at 37° C. (for agonist)and 60 min at 25° C. (for antagonist) in a water bath, and then filteredover either GF/C filters presoaked in 0.5% PEI for 2 hr at roomtemperature (for agonist) or GF/B filters presoaked in 0.5% BSA for 2 hrat

room temperature (for antagonist) with a Filtermate Harvester. Filterswere washed 3× with 0.5 ml of ice-cold wash buffer (50 mM Tris). 50 μlof Microscint 20 was then added, the plates were incubated for 15 min atroom temperature on an orbital shaker, and counted using either aTopCount™ or MicroBeta™ for 1 min/well.

Human 5-HT2C(VSV) radioligand binding assays were performed by thesuccessive addition of 1) 50 μl of either test compound or referenceligand (5-HT) at increasing concentrations, 2) 25 μl of either dilutedagonist ([¹²⁵I]DOI) or antagonist ([³H]mesulergine) radioligand, and 3)25 μl membrane extracts (8 or 1 g/well for agonist and antagonistradioligands, respectively) into the wells of a 96 well plate. Allnecessary dilutions were made in assay buffer (50 mM Tris, 0.1% ascorbicacid, pH 7.4). The final concentrations of [¹²⁵I]DOI and [3H]mesulerginewere 0.35 and 1.5 nM, respectively. Plates were incubated for 60 min ateither 25° C. (for agonist) or 37° C. (for antagonist) in a water bath,and then filtered over GF/B filters presoaked in 0.5% PEI for 2 hr atroom temperature with a Filtermate Harvester. Filters were washed 3×with 0.5 ml of ice-cold wash buffer (50 mM Tris). 50 μl of Microscint 20was then added, the plates were incubated for 15 min at room temperaturean orbital shaker, and counted using either a TopCount™ or MicroBeta™for 1 min/well.

Human 5-HT6 radioligand binding assays were performed by the successiveaddition of 1) 50 μl of either test compound or reference ligand (5-HT)at increasing concentrations, 2) 25 μl of diluted radioligand ([³H]LSD;PerkinElmer NET638), and 3) 25 μl membrane extracts (2.5 g/well) intothe wells of a 96 well plate. All necessary dilutions were made in assaybuffer (50 mM Tris, 4 mM CaCl2, 0.1% ascorbic acid, 10 g/ml saponin, pH7.4). The final concentration of [³H]LSD was 1 nM. Plates were incubatedfor 60 min at 25° C. in a water bath, and then filtered over GF/Bfilters presoaked in 0.5% PEI for 2 hr at room temperature with aFiltermate Harvester. Filters were washed 6× with 0.5 ml of ice-coldwash buffer (50 mM Tris). 50 μl of Microscint 20 was then added, theplates were incubated for 15 min at room temperature an orbital shaker,and counted using either a TopCount™ or MicroBeta™ for 1 min/well.

Example 47 Flipr Assays: Agonist Mode at Human 5-HT2A, 5-HT2B and5-HT2C(VSV)

For assessment of 5-HT2 agonism, Chinese Hamster Ovary (CHOK1) cellsstably expressing human 5-HT2A, 5-HT2B, 5-HT2C(VSV), or 5-HT2C(INI) weregrown to ˜80-90% confluence in a humidified atmosphere at 37° C. with 5%CO₂ in UltraCHO Medium (Lonza, Walkersville, Md.) containing 1% dialyzedfetal bovine serum (FBS), 400 g/ml G418 (Geneticin; Invitrogen,Carlsbad, Calif.), 100 U/ml penicillin, and 100 g/ml streptomycin.Medium was removed by aspiration, cells were washed 1× with PBS, andtrypsinized for 5 min at room temperature. After trypsinization, cellswere diluted with UltraCHO Medium containing 1% dialyzed FBS (with noG418 or antibiotics) and seeded using a microplate dispenser (MatrixWellMate; Thermo Fisher Scientific, Hudson, N.H.) at a density of 22,500cells/well in a volume of 30 l/well onto 384 well black wall/clearbottom, poly-d-lysine coated plates (BD Biocoat; BD Biosciences, SanJose, Calif.). Plates were then incubated overnight in a humidifiedatmosphere at 37° C. with 5% CO₂.

On the day of the experiment, cells were loaded with amembrane-permeable, calcium-sensitive dye (FLIPR Calcium 4 Assay Kit;Molecular Devices, Sunnyvale, Calif.) (prepared according to themanufacturer's instructions) containing 2.5 mM probenecid and incubatedfor 1 hr at 37° C. Plates were removed from the incubator and allowed tocool to room temperature prior to assay (˜15 min). Response to testcompound was measured using a fluorometric imaging plate reader(FLIPR384, Molecular Devices).

Compound plates for FLIPR assays were prepared at either 2 mM (for5-HT2A and 5-HT2C) or 8 mM (for 5-HT2B) in 100% dimethyl sulphoxide(DMSO) and diluted in assay buffer (1×HBSS/20 mM HEPES, pH 7.4) to theappropriate test concentrations. The final in-well concentration of DMSOin all assays was 0.5%. Compounds were tested in duplicate wells using arange of twelve concentrations.

The statistical parameter exported from each well was the maximum peakheight of the response to test compound. The minimum peak height wasthen subtracted from this value, and expressed as a percentage of themean maximal response to 10 M 5-HT. Dose-response curves were generated(GraphPad Prism 4; La Jolla, Calif.) and both potency (EC₅₀) andefficacy (E_(max)) were determined for each test compound.

Example 48 Compound Testing Aequorin Assay

Compounds were tested in duplicate at 10 M concentration, for agonistactivity and 5 μM concentration for antagonist activity at humanserotonin 5-HT2A, 5-HT2C(edited (e)) and 5-HT2C(non-edited (ne))receptors with Aequorin Assay and at human 5-HT6 with cAMP assay. DOIwas tested in parallel on 5-HT2A, 5-HT2C(e) and 5-HT2C(ne) receptorswith Aequorin Assay.

All the compounds exemplified in the examples modulated (i. e. activatedor inhibited) at least one of 5HT2C, 5HT6, and/or 5HT2A more than orequal to 50% at 10 uM concentration.

Compound Testing Flipr assay: Compounds were tested in duplicate, foragonist activity at human serotonin 5-HT2A, 5-HT2B, and 5-HT2C(VSV)Representative examples of the present invention are found to have lownM potency for 5-HT2C receptor and are relatively selective for 5-HT2Creceptor in comparison to other 5-HT receptor subtype and specifically5-HT2A and 5-HT2B. Selectivity is demonstrated in agonist activity assayand receptor binding assays.

Compound Testing binding assay: Compounds were tested in duplicate, inhuman serotonin 5-HT2A, 5-HT2B, 5-HT2C(VSV) and 5-HT6. Representativeexamples of the present invention are found to have low nM affinity for5-HT2C and/or 5-HT6 receptor with Ki's less or equal to 200 nM. Morepreferred are those with Ki's less or equal to 60 nM.

Compound Testing cAMP assay: Compounds were tested in duplicate, foragonist and antagonist activity at human serotonin 5-HT6. Representativeexamples of the present invention are found to have nM EC50 or IC50 for5-HT6.

Representative examples of the present invention are found to haveantagonist activity at 5-HT2A and/or 5-HT2B.

Biological Data

5-HT2C EC₅₀ values of representatives compounds described in theexamples are compiled in table 34. The values have been obtained asdescribed above. A<10 uM, B: 1-<500 nM and C: 500 nM-10 uM. 5-HT6 IC₅₀and/or 5-HT6 EC₅₀ values of representatives compounds in the exampleshace values of <5 uM.

TABLE 34 Cpd 5-HT2C Ex ID EC502-(1-ethyl-6-fluoro-4-(4-fluorobenzyloxy)-1H-indol-3-yl)-N,N-  5  1-14bB dimethylethanamine2-(1-ethyl-6-fluoro-4-(4-methoxybenzyloxy)-1H-indol-3-yl)-N,N-  6  1-15bB dimethylethanamine2-(4-(4-chlorobenzyloxy)-1-ethyl-6-fluoro-1H-indol-3-yl)-N,N-  1  1-10bC dimethylethanamine2-(1-ethyl-6-fluoro-4-(4-(trifluoromethoxy)benzyloxy)-1H-indol-3-yl)-N,N- 2  1-11b C dimethylethanamine2-(1-ethyl-6-fluoro-4-(4-(trifluoromethyl)benzyloxy)-1H-indol-3-yl)-N,N- 3  1-12b C dimethylethanamine2-(1-ethyl-6-fluoro-4-(2-(trifluoromethyl)benzyloxy)-1H-indol-3-yl)-N,N- 4  1-13b C dimethylethanamine2-(1-ethyl-6-fluoro-4-(3-(trifluoromethyl)benzyloxy)-1H-indol-3-yl)-N,N- 7  1-16b C dimethylethanamine2-(3-(2-(dimethylamino)ethyl)-1-ethyl-7-fluoro-1H-indol-4-yloxy)aniline 12  2-3 B 2-(1-ethyl-7-fluoro-4-(2-nitrophenoxy)-1H-indol-3-yl)-N,N- 11  2-2 C dimethylethanamine2-(1-ethyl-6-fluoro-4-(5-fluoro-2-methylbenzyloxy)-1H-indol-3-yl)-N,N- 8  1-17b B dimethylethanamine2-(4-methoxy-1-methyl-7-(pyridin-3-yl)-1H-indol-3-yl)-N,N-  24  6-14 Bdimethylethanamine2-(4-methoxy-1-methyl-7-phenyl-1H-indol-3-yl)-N,N-dimethylethanamine  16 6-6 B 1-ethyl-7-fluoro-3-(2-(phenylamino)ethyl)-1H-indol-4-ol  41 11-7C 2-(1-benzyl-4-(benzyloxy)-7-fluoro-1H-indol-3-yl)-N,N-  25  7-2 Cdimethylethanamine1-benzyl-3-(2-(dimethylamino)ethyl)-7-fluoro-1H-indol-4-ol  26  7-3 C2-(7-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)propan-1-amine  36  9-5 B4-(2-(7-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethyl)morpholine  4311-9 B 2-(6-fluoro-4-methoxy-1-(pyrimidin-2-yl)-1H-indol-3-yl)-N,N-  5215-2 C dimethylethanamine1-ethyl-6-fluoro-3-(2-morpholinoethyl)-1H-indol-4-ol  39 11-5 B1-ethyl-6-fluoro-3-(2-(2-methoxyethylamino)ethyl)-1H-indol-4-ol  44b11-11 B 1-ethyl-6-fluoro-3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-4-ol  4011-6 B7-fluoro-4-methoxy-1-methyl-3-(2-(pyrrolidin-1-yl)ethyl)-1H-indole  4411-10 B 2-(4-methoxy-1-methyl-7-(thiophen-3-yl)-1H-indol-3-yl)-N,N-  23 6-13 C dimethylethanamine2-(4-methoxy-1-methyl-7-(thiophen-2-yl)-1H-indol-3-yl)-N,N-  17  6-7 Cdimethylethanamine2-(7-(furan-2-yl)-4-methoxy-1-methyl-1H-indol-3-yl)-N,N-  18  6-8 Cdimethylethanamine2-(7-(furan-3-yl)-4-methoxy-1-methyl-1H-indol-3-yl)-N,N-  19  6-9 Cdimethylethanamine2-(4-methoxy-1-methyl-7-(1H-pyrrol-2-yl)-1H-indol-3-yl)-N,N-  20  6-10 Cdimethylethanamine3-(3-(2-(dimethylamino)ethyl)-4-methoxy-1-methyl-1H-indol-7-yl)prop-2- 21  6-11 B yn-1-ol3-(2-(dimethylamino)ethyl)-4-methoxy-1-methyl-N-phenyl-1H-indol-7-  22 6-12 B amine2-(4-(benzyloxy)-7-fluoro-1-(naphthalen-2-ylmethyl)-1H-indol-3-yl)-N,N- 29  7-6 B dimethylethanamine2-(4-(benzyloxy)-7-fluoro-1-(thiophen-2-ylmethyl)-1H-indol-3-yl)-N,N- 27  7-4 B dimethylethanamine (E)-methyl3-(3-(2-(dimethylamino)ethyl)-4-methoxy-1-methyl-1H-indol-  83 25-2 B7-yl)acrylate3-(3-(2-(dimethylamino)ethyl)-1-ethyl-7-fluoro-4-methoxy-1H-indol-5-  8627-3 B yl)propan-1-ol2-(4-(benzyloxy)-7-fluoro-1-(furan-2-ylmethyl)-1H-indol-3-yl)-N,N-  8024-1 B dimethylethanamine2-(1-ethyl-4-methoxy-6-phenyl-1H-indol-3-yl)-N,N-dimethylethanamine 16136-6 C4-(benzyloxy)-1-ethyl-6-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-162 37-2 C indole3-(2-(1,4-oxazepan-4-yl)ethyl)-1-ethyl-6-fluoro-1H-indol-4-ol  44c 11-12C3-(2-((2S,6R)-2,6-dimethylmorpholino)ethyl)-1-ethyl-6-fluoro-1H-indol-4- 44e 11-13 C ol3-(2-(3,3-difluoropyrrolidin-1-yl)ethyl)-1-ethyl-6-fluoro-1H-indol-4-ol 44f 11-14 C2-(1-ethyl-6-fluoro-4-(pyridin-4-ylmethoxy)-1H-indol-3-yl)-N,N-  9 1-18b C dimethylethanamineN-benzyl-2-(1-ethyl-7-fluoro-4-methoxy-1H-indol-3-yl)ethanamine  70 20-4B 1-ethyl-6-fluoro-3-(piperidin-3-yl)-1H-indol-4-ol 163 38-4 B2-(1-ethyl-6-fluoro-4-(thiophen-3-ylmethoxy)-1H-indol-3-yl)-N,N-  10 1-19b B dimethylethanamine3-(3-(2-(dimethylamino)ethyl)-1-ethyl-7-fluoro-4-methoxy-1H-indol-5-  8728-4 B yl)propan-1-amine2-(5-(2-(1H-benzo[d]imidazol-2-yl)ethyl)-1-ethyl-7-fluoro-4-methoxy-1H- 88 29-4 B indol-3-yl)-N,N-dimethylethanamine1-ethyl-6-fluoro-3-(1-methylpiperidin-3-yl)-1H-indol-4-ol 164 38-6 C3-(2-(benzylamino)ethyl)-1-ethyl-6-fluoro-1H-indol-4-ol  85-2 26-8 B2-(4-methoxy-1-methyl-7-(phenylsulfonyl)-1H-indol-3-yl)-N,N-  82 25-1 Bdimethylethanamine2-(4-(benzyloxy)-1-ethyl-6-fluoro-1H-indol-3-yl)-N-(3- 114 31-13 B(trifluoromethyl)phenethyl)ethanamine1-ethyl-6-fluoro-3-(2-(piperazin-1-yl)ethyl)-1H-indol-4-ol  44g 11-15 C1-ethyl-6-fluoro-3-(2-(3-(trifluoromethyl)phenethylamino)ethyl)-1H-indol- 85-4 26-10 B 4-ol1-ethyl-6-fluoro-3-(2-(2-phenylpropylamino)ethyl)-1H-indol-4-ol 166b39-6 BN-benzyl-2-(4-(benzyloxy)-1-ethyl-6-fluoro-1H-indol-3-yl)ethanamine 85-1 26-7 CN-benzyl-2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)ethanamine  8930-15 BN-(2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)ethyl)-2,3-dihydro-1H- 90 30-16 B inden-2-amine3-(3-(2-(dimethylamino)ethyl)-4-methoxy-1-methyl-1H-indol-7-yl)propan- 84 25-4 C 1-ol2-(4-(benzyloxy)-1-ethyl-6-fluoro-1H-indol-3-yl)-N-phenethylethanamine 85-3 26-9 CN-(2-chlorobenzyl)-2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-  91 30-17 Byl)ethanamineN-(benzo[d][1,3]dioxol-5-ylmethyl)-2-(4-ethoxy-5-fluoro-1-methyl-1H-  9230-18 B indol-3-yl)ethanamineN-(2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)ethyl)-2,3-dihydro-1H- 93 30-19 B inden-1-amine1-ethyl-6-fluoro-3-(2-(phenethylamino)ethyl)-1H-indol-4-ol  85-5 26-11 B2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)-N-(3-  94 30-20 Bmethylbenzyl)ethanamineN-benzyl-2-(4-(benzyloxy)-1-ethyl-6-fluoro-1H-indol-3-yl)-N- 107 31-6 Bmethylethanamine4-(benzyloxy)-1-ethyl-6-fluoro-3-(2-(isoindolin-2-yl)ethyl)-1H-indole104 31-3 C 1-ethyl-6-fluoro-3-(2-(isoindolin-2-yl)ethyl)-1H-indol-4-ol105 31-4 C 2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)-N-(2-  95 30-21B (trifluoromethyl)benzyl)ethanamine2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)-N-(3-  96 30-22 B(trifluoromethyl)benzyl)ethanamine4-(2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)ethyl)morpholine  9730-23 C(1-(2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)ethyl)pyrrolidin-2-  9830-24 C yl)methanol2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)-N-phenethylethanamine  9930-25 B2-(1-ethyl-7-fluoro-4-methoxy-1H-indol-3-yl)-N-phenethylethanamine  7220-7 B 2-(5-fluoro-1-methyl-4-(thiophen-2-ylmethoxy)-1H-indol-3-yl)-N,N- 11  1-20a B dimethylethanamine2-(benzo[d][1,3]dioxol-5-yl)-N-(2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-100 30-26 B yl)ethyl)ethanamineN-benzyl-2-(1-ethyl-6-fluoro-4-methoxy-1H-indol-3-yl)ethanamine 165 39-4B 2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)-N-(2-(pyridin-2- 10130-27 B yl)ethyl)ethanamine2-(4-ethoxy-5-fluoro-1-methyl-1H-indol-3-yl)-N-(thiophen-2- 102 30-28 Bylmethyl)ethanamine4-ethoxy-5-fluoro-1-methyl-3-(2-(pyrrolidin-1-yl)ethyl)-1H-indole 10330-29 B5-fluoro-4-methoxy-1-methyl-3-(2-(piperazin-1-yl)ethyl)-1H-indole  5717-10 C 2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)-N-(thiophen-2- 15434-6 B ylmethyl)ethanamineN-benzyl-2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethanamine 15534-6 B 2-(5-fluoro-1-methyl-4-phenethoxy-1H-indol-3-yl)-N,N-  66 18-2 Bdimethylethanamine2-(1-ethyl-6-fluoro-4-phenoxy-1H-indol-3-yl)-N,N-dimethylethanamine 11532-2 C3-(2-((1S,4S)-5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)-1-ethyl-108 31-7 C 6-fluoro-1H-indol-4-ol2-(1-ethyl-6-fluoro-4-methoxy-1H-indol-3-yl)-N-(2-(1-ethyl-6-fluoro-4-166 39-5 B methoxy-1H-indol-3-yl)ethyl)-N-methylethanamine2-(4-(2-chlorobenzyloxy)-6-fluoro-1-methyl-1H-indol-3-yl)-N- 148 33-44 Bmethylethanamine 2-(4-(benzyloxy)-1-ethyl-6-fluoro-1H-indol-3-yl)-N-(3-109 31-8 C (trifluoromethyl)benzyl)ethanamine2-(4-(benzyloxy)-1-ethyl-6-fluoro-1H-indol-3-yl)-N-(3- 110 31-9 Cchlorobenzyl)ethanamine2-(1-ethyl-7-fluoro-4-methoxy-1H-indol-3-yl)-N-(1-  73 20-8 Bphenylethyl)ethanamine2-(7-fluoro-4-methoxy-1-methyl-5-phenyl-1H-indol-3-yl)-N-  77 22-5 Bmethylethanamine 2-(1-ethyl-7-fluoro-4-methoxy-1H-indol-3-yl)-N-(2-  7420-9 B methylbenzyl)ethanamineN-(2-chlorobenzyl)-2-(1-ethyl-7-fluoro-4-methoxy-1H-indol-3-  75 20-10 Byl)ethanamineN-(3,4-dimethoxybenzyl)-2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3- 15634-8 B yl)ethanamine2-(4-(4-chlorobenzyloxy)-6-fluoro-1-methyl-1H-indol-3-yl)-N- 149 33-45 Bmethylethanamine2-(4-(3-chlorobenzyloxy)-6-fluoro-1-methyl-1H-indol-3-yl)-N- 150 33-46 Bmethylethanamine3-(2-(benzhydrylamino)ethyl)-1-ethyl-6-fluoro-1H-indol-4-ol 111 31-10 B2-(2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethylamino)-2- 157 34-9B phenylethanol 2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)-N-(1- 15834-10 B phenylethyl)ethanamine2-(4-(3-chlorobenzyloxy)-5-fluoro-1-methyl-1H-indol-3-yl)-N- 116 33-8 Bmethylethanamine3-(2-(3-chlorobenzylamino)ethyl)-1-ethyl-6-fluoro-1H-indol-4-ol 11231-11 B1-ethyl-6-fluoro-3-(2-(3-(trifluoromethyl)benzylamino)ethyl)-1H-indol-4-ol113 31-12 B 2-(4-(4-chlorobenzyloxy)-5-fluoro-1-methyl-1H-indol-3-yl)-N-124 33-20 B methylethanamine2-(5-fluoro-1-methyl-4-(3-(trifluoromethyl)benzyloxy)-1H-indol-3-yl)-N-125 33-21 B methylethanamine2-(5-fluoro-1-methyl-4-(2-methylbenzyloxy)-1H-indol-3-yl)-N- 126 33-22 Bmethylethanamine2-(4-(2-chlorobenzyloxy)-5-fluoro-1-methyl-1H-indol-3-yl)-N- 127 33-23 Bmethylethanamine2-(7-fluoro-4-methoxy-1-methyl-5-phenethyl-1H-indol-3-yl)-N-  78 23-4 CmethylethanamineN-(2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethyl)-4-phenylbutan-1- 60 17-13 B amine2-(5-fluoro-4-(2-fluorobenzyloxy)-1-methyl-1H-indol-3-yl)-N- 128 33-24 Bmethylethanamine2-(5-fluoro-4-(4-methoxyl)henethoxy)-1-methyl-1H-indol-3-yl)-N- 12933-25 B methylethanamine2-(5-fluoro-1-methyl-4-phenethoxy-1H-indol-3-yl)-N-methylethanamine 13033-26 B 3-(2-(benzylamino)ethyl)-5-fluoro-1-methyl-1H-indol-4-ol 15133-47 B 2-(5-fluoro-1-methyl-4-(4-methylbenzyloxy)-1H-indol-3-yl)-N- 13133-27 B methylethanamine2-(5-fluoro-4-(4-fluorophenethoxy)-1-methyl-1H-indol-3-yl)-N- 152 33-28B methylethanamine2-(4-(4-chlorophenethoxy)-5-fluoro-1-methyl-1H-indol-3-yl)-N- 133 33-29B methylethanamine2-(5-(2-cyclohexylethyl)-7-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)-N- 79 23-5 B methylethanamine2-(4-(biphenyl-2-ylmethoxy)-5-fluoro-1-methyl-1H-indol-3-yl)-N- 13433-30 B methylethanamine2-(5-fluoro-1-methyl-4-(2-(trifluoromethyl)benzyloxy)-1H-indol-3-yl)-N-135 33-31 B methylethanamine2-(5-fluoro-1-methyl-4-(1-phenylethoxy)-1H-indol-3-yl)-N- 136 33-32 Bmethylethanamine2-((3-(2-((2-cyanobenzyl)(methyl)amino)ethyl)-5-fluoro-1-methyl-1H- 16035-2 C indol-4-yloxy)methyl)benzonitrile2-(5-fluoro-4-(5-fluoro-2-methylbenzyloxy)-1-methyl-1H-indol-3-yl)-N-137 33-33 B methylethanamine5-fluoro-4-methoxy-1-methyl-3-(2-(4-phenylpiperazin-1-yl)ethyl)-1H-  6117-14 C indole3-(2-(4-(3-chlorophenyl)piperazin-1-yl)ethyl)-5-fluoro-4-methoxy-1-  6217-15 B methyl-1H-indole2-(5-fluoro-1-methyl-4-(2-(trifluoromethoxy)benzyloxy)-1H-indol-3-yl)-N-138 33-34 B methylethanamine2-(5-fluoro-4-(4-fluorobenzyloxy)-1-methyl-1H-indol-3-yl)-N- 139 33-35 Bmethylethanamine2-(5-fluoro-1-methyl-4-(naphthalen-1-ylmethoxy)-1H-indol-3-yl)-N- 14033-36 B methylethanamine1-(2-chlorophenyl)-2-(5-fluoro-1-methyl-3-(2-(methylamino)ethyl)-1H- 14133-37 B indol-4-yloxy)ethanol2-(5-fluoro-1-methyl-4-(4-(methylsulfonyl)benzyloxy)-1H-indol-3-yl)-N-142 33-38 B methylethanamine(S)-N-(2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethyl)-1,2,3,4-  6317-16 B tetrahydronaphthalen-1-amine(S)-N-(2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethyl)-1,2,3,4-  6417-17 B tetrahydronaphthalen-1-amine2-(5-fluoro-4-(naphthalen-1-ylmethoxy)-1-propyl-1H-indol-3-yl)-N- 14333-39 B methylethanamine3-(2-aminoethyl)-5-fluoro-1-((tetrahydro-2H-pyran-2-Amethyl)-1H-indol- 67 19-3 B 4-ol3-(2-aminoethyl)-5-fluoro-1-(2-phenoxyethyl)-1H-indol-4-ol  68a 19-4 BN-(2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethyl)-3-(4-  65 17-18 Bmethylpiperazin-1-yl)aniline2-(5-fluoro-1-methyl-4-(quinolin-8-ylmethoxy)-1H-indol-3-yl)-N- 11733-13 B methylethanamine2-(5-fluoro-1-methyl-4-(2-phenoxyethoxy)-1H-indol-3-yl)-N- 118 33-14 Bmethylethanamine8-chloro-3-(2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethyl)-1-  5517-8 B methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine2-(5-fluoro-4-(4-fluorobenzyloxy)-1-propyl-1H-indol-3-yl)-N- 119 33-15 Bmethylethanamine2-(5-fluoro-4-(4-methylbenzyloxy)-1-propyl-1H-indol-3-yl)-N- 120 33-16 Bmethylethanamine2-(5-fluoro-1-methyl-4-(2-methylphenethoxy)-1H-indol-3-yl)-N- 121 33-17B methylethanamine3-(2-aminoethyl)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-5-  68b19-5 B fluoro-1H-indol-4-ol1-(2-(5-fluoro-4-methoxy-1-methyl-1H-indol-3-yl)ethyl)pyrrolidine-2-  5617-9 C carboxamide2-(4-(2-chlorophenethoxy)-5-fluoro-1-methyl-1H-indol-3-yl)-N- 123 33-19C methylethanamine2-(4-(2,4-dichlorobenzyloxy)-5-fluoro-1-methyl-1H-indol-3-yl)-N- 15233-48 A methylethanamine2-(3-(2-aminoethyl)-5-fluoro-4-hydroxy-1H-indol-1-yl)-N,N-  68c 19-6 Adiethylacetamide2-(3-(2-aminoethyl)-5-fluoro-4-hydroxy-1H-indol-1-yl)acetamide  68d 19-7A 5-fluoro-3-(2-((6-methylpyridin-2-Amethylamino)ethyl)-1-propyl-1H- 65a 17-19 A indol-4-ol5-fluoro-1-methyl-3-(2-((6-methylpyridin-211)methylamino)ethyl)-1H-  65b17-20 A indol-4-ol2-(4-(4-chlorobenzyloxy)-5-fluoro-1-propyl-1H-indol-3-yl)ethanamine  66b18-3 A2-(7-propyl-3,7-dihydro-2H-[1,4]dioxino[2,3-e]indol-9-yl)ethanamine 16740-6 A2-(4-(4-chloro-3-(trifluoromethoxy)benzyloxy)-5-fluoro-1-methyl-1H-indol-153 33-49 A 3-yl)-N-methylethanamine

Example 47 Acute Food Intake Assay

Male, Sprague Dawley rats, weighing between 280 and 320 g serve assubjects in this experiment. All rats are allowed to acclimate to thevivarium for at least 1 week prior to study start. Rats are housedsingularly in home cages with a layer of absorbent paper covering thefloor. The cage does not contain any form of bedding. Water is availableat all times by water bottle and food is returned to each animal in theform of pelleted chow. The container along with the food contents isweighed prior to adding it to the cage and is then reweighed at 1, 2, 6and 24 hours later. Any spilled food is collected and returned to thefeeding container prior to weighing. All animals are fasted for 16 hoursovernight prior to a single oral gavage dosing (vehicle, plus one tothree dose groups). Body weight is measured prior to dosing. Food isreturned to all animals ad libitum 2 hours after dosing. Total amount offood consumed is measured for each animal at t=1, 2, 6 and 24 hoursafter return of food. Body weight is measured again at 24 hours. Allanimals are clinically observed throughout the study for unusualbehavior, mortality or morbidity. The amount of food consumed at eachtime point and body weight are used as dependent measures in the study.

Conditioned Avoidance Response

Conditioned Avoidance Response (CAR) training is conducted in Coulbourntwo way shuttle chambers. Male, Wistar rats, weighing between 250 and300 g serve as subjects in the experiments. Rats are habituated to thetesting room for 60 minutes prior to behavioral testing. Trainingconsists of a 5 minute habituation period, where the animals are allowedto freely explore both left and right hand chambers. The habituationperiod is followed by repeated pairings of a CS (light and 80 dB tone)followed 10 seconds later by a 0.8 mA footshock which is terminated uponthe animal's escape to the adjacent chamber, or after 10 seconds. If therat moves to the safe, adjacent chamber within 10 seconds, before thetermination of the CS, the shock is avoided and the trial is recorded asan avoidance. If the rat moves to the safe compartment within the first10 seconds of the shock, the trial is recorded as an escape. If the ratfails to move to the safe compartment during the entire 10 seconds ofthe shock, the trial is recorded as a failure. Thirty trials are givenin each daily training session, and rats are trained until they havereached a criterion of 80% correct avoidance responses on threeconsecutive days. A test session in which rats are tested on CAR in thepresence of compound is conducted after criterion is achieved. On thetest day, rats are habituated to the room, then weighed and gavaged withcompound (vehicle, plus three dose groups) 30 to 60 minutes beforetraining. Training is conducted as described above. The number ofcrossings made between chambers during the habituation period, as wellas the number of avoidances, escapes and failures is recorded for eachrat across training days and on the test day. Percent avoidance, failureand escape are calculated and means and SEM's generated. Data areanalyzed using one-way ANOVA and SNK post-hoc analysis as appropriate.

Prepulse Inhibition

Male, Wistar rats, weighing between 250 and 300 g serve as subjects inthe experiments. Rats are habituated to the testing room for 60-120minutes prior to behavioral testing. Rats are randomized to treatmentgroups based on a pre-determined startle response, weighed, gavaged withcompound (vehicle, plus three dose groups) and then placed in prepulseinhibition chambers. Kinder Scientific chambers are used for theexperiment. Kinder software controls the delivery of all stimuli to theanimals and records the response. Training consists of a 5 minutehabituation period during which a 65 dB background noise is continuouslypresent. This background noise remains present throughout the entiretesting session. After the habituation period, the rats receive a seriesof five, 40-ms, 120 dB bursts of white noise to partially habituate theanimals to the startle-eliciting stimulus. After these stimuli arepresented, the training session proper begins. For the training session,a 10-ms prepulse at 68, 71 or 80 dB, followed 100-ms later by a 120 dB,40-ms startle stimulus is presented. Startle stimulus and no-stimulustrials are also included in the testing session. The stimuli arepresented in random order with interstimulus intervals averaging 15seconds. Levels of prepulse inhibition are determined by the formula(100−((prepulse pulse/alone×100)) and are expressed as percentinhibition.

Spontaneous Locomotion

Male, Wistar rats, weighing between 250 and 300 g serve as subjects inthe experiments. Rats are habituated to the testing room for 60-120minutes prior to behavioral testing. Rats are weighed and gavaged withcompound (vehicle, plus three dose groups) and are then placed inautomated activity monitoring chambers (Kinder Scientific). The activitylevels of the rat, including horizontal movements, total distance moved,total rest time, fine movements and rears are recorded for twoconsecutive hours. The rats are then removed from the apparatus andreturned to their home cages.

Drug-Induced Hyperlocomotion

Male, Wistar rats, weighing between 250 and 300 g serve as subjects inthe experiments. Rats are habituated to the testing room for 60-120minutes prior to behavioral testing. Fifteen to thirty minutes prior totesting, rats are weighed and gavaged with compound (vehicle, plus threedose groups) and are placed in automated activity monitoring chambers(Kinder Scientific) for a 30 minute baseline period. At the end of thebaseline period, the animals are removed from the chamber and injectedwith a psychotomimetic (eg, PCP or d-amphetamine). The rats are thenreturned to the chambers where their activity levels are monitored fortwo consecutive hours.

Novel Object Recognition

Male, Wistar rats, weighing between 250 and 300 g serve as subjects forthe experiments. Rats are habituated to the testing room for 60-120minutes prior to behavioral testing. Testing is conducted in large,circular arenas (80 cm in diameter). Training consists of threesessions: habituation, sample and test. For habituation, the rats areplaced into an empty test chamber and allowed to explore for a 10 minuteperiod. The sample trial, in which two large, identical objects areplaced inside the arena, takes place 24 hours after habituation. Theanimal is placed inside the arena with the two identical objects andallowed to explore for 5 minutes. The number of approaches and the timespent sniffing each of the objects is recorded by automated software(CleverSys, Inc). Twenty-four hours after the sample phase, the rat isreturned to the arena for the test trial. For the test trial, twoobjects, one familiar object that the animal saw in the sample phase,and one novel object that the animal has not seen before, are placedinside the arena. The animal is placed into the arena with the objectsand allowed to explore for a 5 minute period. The number of approachesand time spent sniffing each of the objects is recorded. Compound(vehicle plus three dose groups, via oral gavage) may be administeredeither before or after the sample trial, or before the test trial. Thetime the rat spends sniffing each object is used to calculate adiscrimination index ((time exploring novel−time exploringfamiliar)/total exploration time) that is used to determine preferencefor the familiar versus the novel objects.

The disclosures of each and every patent, patent application andpublication cited herein are hereby incorporated herein by reference intheir entirety.

Although the invention has been disclosed with reference to specificembodiments, it is apparent that other embodiments and variations of theinvention may be devised by others skilled in the art without departingfrom the true spirit and scope of the invention. The claims are intendedto be construed to include all such embodiments and equivalentvariations.

What is claimed is:
 1. A compound selected from the following formula:

wherein R^(1a) and R^(2a) are each independently selected from H,optionally substituted C₁₋₈ alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted arylalkyl,optionally substituted heteroaralalkyl, optionally substitutedcycloalkyl, optionally substituted heterocyclyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocycloalkyl; R³ is selectedfrom H, optionally substituted C₁₋₈ alkyl, optionally substituted C₃₋₈cycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, halogen, or—C(O)NR^(d)R^(d′); W is

optionally substituted aryl, optionally substituted heteroaryl,optionally substituted arylC₂-C₆alkyl, optionally substitutedheterocyclyl, optionally substituted cycloalkyl; optionally substitutedheteroarylalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocycloalkyl, optionally substituted arylheteroalkyl,optionally substituted heteroarylheteroalkyl, optionally substitutedheterocyclylheteroalkyl, optionally substituted cycloalkylheteroalkyl,-alkyl-O—C₀₋₂alkyl-aryl, -alkyl-O—C₀₋₂alkyl-heteroaryl,—C(O)NR^(d)R^(d′), C₁ alkyl substituted with —C(O)NR^(d)R^(d′), or C₂₋₈alkyl substituted with —NR^(d)R^(d′), —C(O)NR^(d)R^(d′) or —OR^(d); A isoptionally substituted C₁₋₄ alkylene, optionally substitutedcycloalkylene, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted arylene, optionally substitutedheteroarylene, or optionally substituted heterocycloalkylene, whereinarylene or heteroarylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, C₃₋₈ cycloalkyl, —OR^(d), C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂arylalkyl, —S(O)₀₋₂ heteroarylalkyl), —S(O)₀₋₂ cycloalkyl, —S(O)₀₋₂heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″)—NR^(d)C(O)OR^(b), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d), whereinalkylene and cycloalkylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, oxo, optionally substituted C₁₋₆ alkyl,—S(O)₀₋₂alkyl, —OR^(d) and —NR^(d)R^(d′), aryl or heteroaryl, and C₃-C₈cycloalkyl or 4-8 membered heterocyle; R⁴ is selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted C₁₋₈ heteroalkyl,optionally substituted C₂₋₈ alkenyl, C₂₋₈ alkynyl, —S(O)₂ alkyl, —S(O)₂heteroalkyl, —S(O)₂ aryl, —S(O)₂ heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂heterocyclyl, —S(O)₂ heterocycloalkyl, —S(O)₂ arylalkyl, —S(O)₂heteroarylalkyl, —S(O)₂ cycloalkyalkyl, formyl, —OR^(d), —NR^(d)R^(d′),—C(O)OR^(a), —C(O)NR^(d)R^(d′), —S(O)₂NR^(d)R^(d′), amine-substitutedC₂₋₆ alkyl, NR^(d′)R^(d″)-substituted C₂₋₆ alkyl, C₃₋₈ cycloalkyl,heterocyclyl, cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl,arylalkyl, and heteroarylalkyl, wherein the alkyl, cycloalkyl andheterocyclyl are optionally substituted with 1-3 substituents, halo,alkyl, haloalkyl, heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryland herteroaryl are optionally substituted with 1-3 substituents, eachof which is independently selected from the group consisting of halogen,alkyl, heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈haloalkoxy, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂-arylalkyl, —S(O)₀₋₂-heteroarylalkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —OR^(d), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), optionally substituted—C₁alkyl-C(O)NR^(e)R^(f), —C₂alkyl-O-aryl, —C₂alkyl-O-heteroaryl,—C₁alkyl-heterocyclyl, —C₁alkyl-cycloalkyl, cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl-NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d); R⁵ isselected from H, halo, and R⁶; each R⁶ is independently selected fromhalo, C₁₋₈ alkyl, aryl, heteroaryl, heteroalkyl, C₃₋₈ cycloalkyl,heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkyl, —SH, —OR^(d), C₁₋₈ haloalkoxy, C₁₋₈ haloalkyl,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂arylalkyl, —S(O)₀₋₂ heteroarylalkyl, —S(O)₀₋₂ cycloalkyl, —S(O)₀₋₂heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),—NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂—C₁₋₄alkyl-aryl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted; each of R⁷ and R8 isindependently H, optionally substituted C₁₋₈ alkyl or fluoro; or R⁷ andR⁸ can, together with the carbon to which they are attached, form aring; R^(a), and R^(b) are each independently selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, optionally substituted cycloalkylalkyl and optionallysubstituted heterocycloalkyl; R^(d), R^(d′), and R^(d″) are eachindependently selected from H and R^(a), or when taken together with theatom to which they are attached two of R^(d), R^(d′) and R^(d″) form a4-8 membered heterocyclic moiety; g is 1, 2 or 3; m is 0, 1, 2, 3, 4 or5; and wherein when m is 0, at least one of R⁷ or R⁸ is not H.
 2. Thecompound of claim 1, wherein R^(1a) and R^(2a) are each independentlyselected from H, C₁₋₈ alkyl, or optionally substituted aryl.
 3. Thecompound of claim 1, wherein R³ is selected from H, and optionallysubstituted C₁₋₈ alkyl.
 4. The compound of claim 1, wherein R⁴ isselected from optionally substituted C₁₋₈ alkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, amine-substituted C₂₋₆ alkyl,NR^(d′)R^(d″)-substituted C₂₋₆ alkyl, —S(O)₂ alkyl, —S(O)₂ arylalkyl,—S(O)₂ heteroarylalkyl, —S(O)₂ aryl, —S(O)₂ heteroaryl, —S(O)₂cycloalkyl, —S(O)₂ heterocycloalkyl, —S(O)₂ heterocycloalkylalkyl,—S(O)₂ cycloalkylalkyl, optionally substituted —C₁alkyl-C(O)NR^(e)R^(f),—C₂alkyl-O-aryl, —C₂alkyl-O-heteroaryl, —C₁alkyl-heterocyclyl, and—C₁alkyl-cycloalkyl.
 5. The compound of claim 1, wherein W isarylC₂₋₈alkyl optionally substituted with —OR^(d), —NR^(d)R^(d′), or—C(O)NR^(d)R^(d′).
 6. The compound of claim 1, wherein W is optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl, oroptionally substituted aryl.
 7. The compound of claim 1, wherein W is—(CH₂)₂—O-phenyl.
 8. The compound of claim 1, wherein the compound isselected from

wherein Ar is optionally substituted aryl or optionally substitutedheteroaryl.
 9. A compound selected from the following formula:

wherein g is 1, 2 or 3; R^(1a) is selected from H, optionallysubstituted C₁₋₈ alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted arylalkyl, optionallysubstituted heteroarylalkyl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocycloalkyl; Q is selectedfrom aryl, heteroaryl, arylalkyl, heterocycloalkyl, heteroarylalkyl,alkyl-C(O)NR^(e)R^(f), alkyl-C(O)-heterocyclyl, heterocycloalkyl-alkyl,cycloalkyl, cycloalkylaryl, cycloalkylalkyl, arylheteroalkyl, andheteroarylheteroalkyl, wherein Q is optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of optionally substituted —C₁₋₆heteroalkyl, halogen, C₃₋₈cycloalkyl, —OR^(d), C₁₋₈ haloalkoxy, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂aryl, —S(O)₀₋₂ heteroaryl, —S(O)₀₋₂ arylalkyl, —S(O)₀₋₂heteroarylalkyl), —S(O)₀₋₂ cycloalkyl, —S(O)₀₋₂ heterocycloalkyl,—S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂ cycloalkylalkyl,—OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b),—NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl,—NR^(d)S(O)₂cycloalkyl, —NR^(d)S(O)₂heterocycloalkyl,—NR^(d)S(O)₂-arylalkyl, —NR^(d)S(O)₂-heteroarylalkyl,—NR^(d)S(O)₂-cycloalkylalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, —NR^(d)R^(d′), aryl, heteroaryl, heterocyclyl, -alkyl-OR^(d),optionally substituted —C₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′),and —C(O), wherein R^(e) and R^(f) are selected from the same groups asR¹ and R², respectively; R³ is selected from H, optionally substitutedC₁₋₈ alkyl, optionally substituted C₃₋₈ cycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, halogen, or C(O)NR^(d)R^(d′); W² is hydrogen,optionally substituted C₁₋₈ alkyl, optionally substituted aryl,optionally substituted arylalkyl, optionally substituted heteroaryl,optionally substituted heterocyclyl, optionally substitutedheteroarylalkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocycloalkyl, or—C(O)NR^(d)R^(d′); A is optionally substituted C₁₋₄ alkylene, optionallysubstituted cycloalkylene, optionally substituted arylene, optionallysubstituted heteroarylene, wherein arylene or heteroarylene areoptionally substituted with 1-3 substituents, each of which isindependently selected from the group consisting of halogen, optionallysubstituted aryl, optionally substituted heteroaryl, C₃₋₈ cycloalkyl,—OR^(d), C₁₋₈ haloalkoxy, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂heteroaryl, —S(O)₀₋₂ arylalkyl, —S(O)₀₋₂ heteroarylalkyl),—OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(a),—NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl,—NR^(d)S(O)₂cycloalkyl, —NR^(d)S(O)₂heterocycloalkyl,—NR^(d)S(O)₂-arylalkyl, —NR^(d)S(O)₂—C₁₋₄alkyl-heteroaryl,—NR^(d)S(O)₂—C₁₋₄alkyl-cycloalkyl,—NR^(d)S(O)₂—C₁₋₄alkyl-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substitutedC₁₋₆ alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d),wherein alkylene and cycloalkylene are optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, oxo, optionally substituted C₁₋₆ alkyl,—S(O)₀₋₂alkyl, —OR^(d) and —NR^(d)R^(d′), aryl or heteroaryl, and C₃-C₈cycloalkyl or 4-8 membered heterocyle; R⁴ is selected from optionallysubstituted C₁₋₈ alkyl, optionally substituted C₁₋₈ heteroalkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, —S(O)₂ alkyl, —S(O)₂ heteroalkyl, —S(O)₂ aryl,—S(O)₂ heteroaryl, —S(O)₂ cycloalkyl, —S(O)₂ heterocyclyl, —S(O)₂heterocycloalkyl, —S(O)₂ arylalkyl, —S(O)₂ heteroarylalkyl, —S(O)₂cycloalkyalkyl, formyl, —OR^(d), —NR^(d)R^(d′), —C(O)OR^(a),—C(O)NR^(d)R^(d′), —S(O)₂NR^(d)R^(d′), C₃₋₈ cycloalkyl, heterocyclyl,cycloalkylalkyl, heteocyclylalkyl, aryl, heteroaryl, arylalkyl, andheteroarylalkyl, wherein the alkyl, cycloalkyl and heterocyclyl areoptionally substituted with 1-3 substituents, halo, alkyl, haloalkyl,heteroalkyl, —OR^(d), —NR^(d)R^(d′), and wherein aryl and herteroarylare optionally substituted with 1-3 substituents, each of which isindependently selected from the group consisting of halogen, alkyl,heteroalkyl, cycloalkyl, heterocyclyl, —OR^(d), —SH, C₁₋₈ haloalkoxy,—S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂-arylalkyl, —S(O)₀₋₂-heteroarylalkyl, —OC(O)NR^(d)R^(d′),—NR^(d)C(O)NR^(d′)R^(d″), —NR^(d)C(O)OR^(b), —OR^(d), —NR^(d)S(O)₂alkyl,—NR^(d)S(O)₂aryl, —NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(d)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), optionally substituted—C₁alkyl-C(O)NR^(e)R^(f), —C₁alkyl-O-aryl, —C₁alkyl-O-heteroaryl,—C₁alkyl-heterocyclyl, —C₁alkyl-cycloalkyl, cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), optionally substituted C₁₋₆alkyl, —NR^(d)C(O)R^(a), —C(O)NR^(d)R^(d′), and —C(O)OR^(d); each R⁶ isindependently selected from halo, C₁₋₈ alkyl, aryl, heteroaryl,heteroalkyl, C₃₋₈ cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkyl, —SH, —OR^(d), C₁₋₈ haloalkoxy, C₁₋₈haloalkyl, —S(O)₀₋₂ C₁₋₈ alkyl, —S(O)₀₋₂ aryl, —S(O)₀₋₂ heteroaryl,—S(O)₀₋₂ arylalkyl, —S(O)₀₋₂ heteroarylalkyl, —S(O)₀₋₂ cycloalkyl,—S(O)₀₋₂ heterocycloalkyl, —S(O)₀₋₂ heterocycloalkylalkyl, —S(O)₀₋₂cycloalkylalkyl, —OC(O)NR^(d)R^(d′), —NR^(d)C(O)NR^(d′)R^(d″),NR^(d)C(O)OR^(a), —NR^(d)S(O)₂alkyl, —NR^(d)S(O)₂aryl,—NR^(d)S(O)₂heteroaryl, —NR^(d)S(O)₂cycloalkyl,—NR^(d)S(O)₂heterocycloalkyl, —NR^(d)S(O)₂-arylalkyl,—NR^(d)S(O)₂-heteroarylalkyl, —NR^(d)S(O)₂-cycloalkylalkyl,—NR^(a)S(O)₂-heterocycloalkyl, —SO₂NR^(d)R^(d′), cyano, nitro, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, —NR^(d)R^(d′), —C₁₋₄alkyl-NR^(d)R^(d′),optionally substituted C₁₋₆ alkyl, —NR^(d)C(O)R^(a), C(O)NR^(d)R^(d′),and —C(O)OR^(d); wherein alkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl are optionally substituted; R^(a), and R^(b) are eachindependently selected from optionally substituted C₁₋₈ alkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted C₃₋₈ cycloalkyl, optionally substitutedarylalkyl, optionally substituted heteroarylalkyl, optionallysubstituted cycloalkylalkyl and optionally substituted heterocycloalkyl;R^(d), R^(d′), and R^(d″) are each independently selected from H andR^(a), or when taken together with the atom to which they are attachedtwo of R^(d), R^(d′) and R^(d″) form a 4-8 membered heterocyclic moiety.10. The compound of claim 9, wherein R^(1a) is selected from H,optionally substituted C₁₋₈ alkyl, and optionally substituted aryl. 11.The compound of claim 9, wherein A is optionally substituted C₁₋₄alkylene, wherein the C₁₋₄ alkylene is optionally substituted with 1-3substituents, each of which is independently selected from the groupconsisting of halogen, hydroxyl, optionally substituted C₁₋₆ alkyl, C₁₋₈alkoxy, —SO₂ alkyl, and —NR^(d)R^(d′).
 12. A method for the treatment ofobesity in a subject, the method comprising administering to the subjecta compound of formulae I or VII, such that obesity is treated in thesubject.
 13. A method for suppressing appetite in a subject, the methodcomprising administering to the subject a compound of formulae I or VII,such that appetite is suppressed in the subject.
 14. A method for thetreatment of schizophrenia or psychosis in a subject, the methodcomprising administering to the subject a compound of formulae I or VII,such that schizophrenia or psychosis is treated in the subject.
 15. Amethod for the treatment of diabetes in a subject, the method comprisingadministering to the subject a compound of formulae I or VII, such thatdiabetes is treated in the subject.
 16. A method of modulating aserotonin receptor, the method comprising contacting a serotoninreceptor with a compound of formulae I or VII.